Revisiting the BRCA-pathway through the lens of replication gap suppression: “Gaps determine therapy response in BRCA mutant cancer”

doi:10.1016/j.dnarep.2021.103209

DNA Repair

Volume 107, November 2021, 103209

https://doi.org/10.1016/j.dnarep.2021.103209 Get rights and content

Abstract

The toxic lesion emanating from chemotherapy that targets the DNA was initially debated, but eventually the DNA double strand break (DSB) ultimately prevailed. The reasoning was in part based on the perception that repairing a fractured chromosome necessitated intricate processing or condemned the cell to death. Genetic evidence for the DSB model was also provided by the extreme sensitivity of cells that were deficient in DSB repair. In particular, sensitivity characterized cells harboring mutations in the hereditary breast/ovarian cancer genes, BRCA1 or BRCA2, that function in the repair of DSBs by homologous recombination (HR). Along with functions in HR, BRCA proteins were found to prevent DSBs by protecting stalled replication forks from nuclease degradation. Coming full-circle, BRCA mutant cancer cells that gained resistance to genotoxic chemotherapy often displayed restored DNA repair by HR and/or restored fork protection (FP) implicating that the therapy was tolerated when DSB repair was intact or DSBs were prevented. Despite this well-supported paradigm that has been the impetus for targeted cancer therapy, here we argue that the toxic DNA lesion conferring response is instead single stranded DNA (ssDNA) gaps. We discuss the evidence that persistent ssDNA gaps formed in the wake of DNA replication rather than DSBs are responsible for cell killing following treatment with genotoxic chemotherapeutic agents. We also highlight that proteins, such as BRCA1, BRCA2, and RAD51 known for canonical DSB repair also have critical roles in normal replication as well as replication gap suppression (RGS) and repair. We review the literature that supports the idea that widespread gap induction proximal to treatment triggers apoptosis in a process that does not need or stem from DSB induction. Lastly, we discuss the clinical evidence for gaps and how to exploit them to enhance genotoxic chemotherapy response.

Section snippets

Overview, taking on the DSB dogma

The concept that DSBs are lethal has been widely described [1,2] and contributed to the idea that DSBs are the killing lesion emanating from genotoxic chemotherapy [3]. While defects in DSB repair (DSBR) often characterize cells with high sensitivity to genotoxic therapy, this correlation may not be causation and requires consideration of other underlying defects. Here, we review this DSB dogma and present a counter proposition that single stranded DNA (ssDNA) is the defining toxic lesion that

Genotoxic chemotherapy generates a range of lesions, but the DSB is considered the most toxic one

Historically, genotoxic chemotherapy such as ionizing radiation (IR) was found to induce a range of lesions [4]. In addition to DSBs, in which both strands of the DNA phosphodiester backbone are broken, ssDNA breaks (SSBs), nicks, or gaps were identified. Nicks interrupt a single strand of the DNA phosphodiester backbone and maintain clean 3′-hydroxyl ends that enable repair synthesis or ligation, whereas SSBs carry damaged ends that require processing prior to ligation [5]. Larger regions of

BRCA deficiency is a model of chemotherapy sensitivity and is defective in DNA repair

A resounding finding that validated the presumption that DSBs were the sensitizing lesion stemming from cancer therapies was based on the BRCA model of chemosensitivity. Not only were tumors with mutations in the hereditary breast and ovarian cancer genes BRCA1 or BRCA2 hypersensitive to genotoxic chemotherapy [[16], [17], [18]], but also a key feature of BRCA deficiency was the failure to repair DSBs by homologous recombination (HR) [19,20] and reviewed in [21]. Given the BRCA deficiency model

Could something else confer chemotherapy response?

It seems implausible in the face of all this evidence that alternative mechanisms contribute to or solely cause sensitivity to genotoxic agents. Here, it is important to consider the emergence of nonconforming outlier cases. These models present the argument that HR and/or FP alone may not be sufficient to mediate chemotherapy response to genotoxic agents. For example, initially FP alone was found to confer chemoresistance in BRCA2 deficient cancer [60]. However, with the identification of

BRCA deficient cancer cells have defects in replication gap suppression (RGS)

The argument that a loss of distinct function aside from HR and FP confers chemosensitivity in BRCA deficient cells requires identification of another defect. Here, there is a growing body of research indicating that BRCA-RAD51 pathway functions in DNA replication [65] with its deficiency generating replication restraint defects and gap formation [45,47,64,[66], [67], [68], [69], [70], [71], [72], [73]]. Gaps in BRCA deficient Xenopus extracts were initially visualized on newly synthesized

When BRCA deficient cancer gain resistance, RGS is also restored

In addition to the emerging evidence that indicates that gaps are separate lesions behind the fork created by genotoxic chemotherapy and suppressed by the BRCA-RAD51 pathway, RGS is linked to therapy resistance. In particular, ssDNA gaps accurately predict chemo-response and RGS predicts resistance in cell culture, the TCGA patient database, and patient xenografts. Although the molecular triggers are different in the BRCA1 and BRCA2 backgrounds, the fundamentals of the chemoresistance

Gaps are distinct from degraded forks

Conceivably gaps seed fork degradation or vice versa and therefore are ultimately the same thing. Inconsistent with this idea, gaps are observed in non-challenged BRCA-RAD51 deficient cells that show high PAR in S phase consistent with OFP defects [62]. Moreover, in response to stress, gaps are observed behind the replication fork - not at the replication fork- are not likely to seed fork degradation or the collapse of forks. Specifically, gaps arise in BRCA deficient cells that fail to

RGS is uniquely coupled to chemotherapy response

In support of the framework that replication gaps are the sensitizing lesion as opposed to DSBs, there are several emerging examples. First, the DSB model requires complexity because in some cases, HR proficient [59] or FP proficient [60] cells are as expected chemoresistant, but in other cases HR proficient [64,76], FP proficient [45] or HR and FP proficient [62,63,76] cells are unexpectedly chemosensitive. Thus, HR and FP vary in their relation to PARPi response, a wrinkle requiring the model

Cancer therapies generate lots of ssDNA

As described above, initially ssDNA in the form of nicks, SSBs or gaps were considered in the toxicity of genotoxic agents because ssDNA was the predominate lesion identified following diverse chemotherapeutic agents [138,139]. For example, etoposide was found to induce 30-fold more SSBs than DSBs, and ionizing radiation (IR), was found to induce 100 nicks for each DSB [34,9,140,141]. Even when DSBs were considered the major cause of therapy-induced toxicity, it was observed that SSBs

Are DSBs relevant to the response to genotoxic agents?

While the field has “grown up” with the idea that DSBs are toxic and underlie the killing induced by genotoxic chemotherapy at least with respect to BRCA deficiency, it is worth a brief discussion about the universality of this concept. While it is not clear that a non-repairable, or erroneously repaired DSB induced by endonucleases has physiological relevance with respect to genotoxic chemotherapy, it is important to appreciate that findings in such model systems impacted the field. Initial

Is ssDNA toxic?

Given that ssDNA forms as part of many biological processes and can be readily repaired [193], gaps emanating from genotoxic agents would be expected to be tolerated unless distinct in some way. Genotoxins could invoke toxicity because gaps develop in genomic regions escaping repair, checkpoint or cell quality control mechanisms. Unlike gaps at a stalled fork, gaps behind the fork could be overlooked or lack coordination with cellular checkpoint responses that elicit a global replication arrest

Declaration of Competing Interest

The author reports no declaration of interest.

Acknowledgments

I greatly appreciate the help of the Cantor lab with special thanks to Drs. Nicholas Panzarino and Jenna Whalen. I am also grateful to Drs. Orlando Scharer, Jim Haber, and John Petrini for discussions and critical comments. Funding includes R01 CA254037 and CA247232.

References (210)

R.P. Wong et al.
Daughter-strand gaps in DNA replication - substrates of lesion processing and initiators of distress signalling
DNA Repair (Amst)
(2021)
A. Quinet et al.
To skip or not to skip: choosing repriming to tolerate DNA damage
Mol. Cell
(2021)
M.K. Weil et al.
PARP inhibitor treatment in ovarian and breast cancer
Curr. Probl. Cancer
(2011)
R. Fridlich et al.
BRCA1 and BRCA2 protect against oxidative DNA damage converted into double-strand breaks during DNA replication
DNA Repair (Amst)
(2015)
S. Fekairi
Human SLX4 is a Holliday junction resolvase subunit that binds multiple DNA repair/recombination endonucleases
Cell
(2009)
E. Petermann et al.
Hydroxyurea-stalled replication forks become progressively inactivated and require two different RAD51-mediated pathways for restart and repair
Mol. Cell
(2010)
W.P. Roos et al.
DNA damage-induced cell death by apoptosis
Trends Mol. Med.
(2006)
T. Helleday
The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings
Mol. Oncol.
(2011)
K. Schlacher
Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11
Cell
(2011)
K. Schlacher et al.
A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51-BRCA1/2
Cancer Cell
(2012)

G. Lossaint

FANCD2 binds MCM proteins and controls replisome function upon activation of s phase checkpoint signaling

Mol. Cell

(2013)

J. Spies

Nek1 regulates Rad54 to orchestrate homologous recombination and replication fork stability

Mol. Cell

(2016)

M. Peng

Opposing roles of FANCJ and HLTF protect forks and restrain replication during stress

Cell Rep.

(2018)

S.F. Bunting

53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks

Cell

(2010)

A.T. Wang

A dominant mutation in human RAD51 reveals its function in DNA interstrand crosslink repair independent of homologous recombination

Mol. Cell

(2015)

V. Costanzo

Brca2, Rad51 and Mre11: performing balancing acts on replication forks

DNA Repair (Amst)

(2011)

J. Henry-Mowatt

XRCC3 and Rad51 modulate replication fork progression on damaged vertebrate chromosomes

Mol. Cell

(2003)

A. Ait Saada et al.

Preserving replication fork integrity and competence via the homologous recombination pathway

DNA Repair (Amst)

(2018)

B. Eppink

The response of mammalian cells to UV-light reveals Rad54-dependent and independent pathways of homologous recombination

DNA Repair (Amst)

(2011)

K.K. Khanna et al.

DNA double-strand breaks: signaling, repair and the cancer connection

Nat. Genet.

(2001)

S.P. Jackson et al.

The DNA-damage response in human biology and disease

Nature

(2009)

E. Mladenov et al.

DNA double-strand break repair as determinant of cellular radiosensitivity to killing and target in radiation therapy

Front. Oncol.

(2013)

P.L. Olive

The role of DNA single- and double-strand breaks in cell killing by ionizing radiation

Radiat. Res.

(1998)

N. Maizels et al.

Initiation of homologous recombination at DNA nicks

Nucleic Acids Res.

(2018)

W.L. Kuo et al.

Neocarzinostatin-mediated DNA damage and repair in wild-type and repair-deficient Chinese hamster ovary cells

Cancer Res.

(1984)

A. Muslimovic et al.

Numerical analysis of etoposide induced DNA breaks

PLoS One

(2009)

C. Lundin

Methyl methanesulfonate (MMS) produces heat-labile DNA damage but no detectable in vivo DNA double-strand breaks

Nucleic Acids Res.

(2005)

T.C. Karagiannis et al.

Double-strand breaks: signaling pathways and repair mechanisms

Cell. Mol. Life Sci.

(2004)

O.A. Sedelnikova et al.

Histone H2AX in DNA damage and repair

Cancer Biol. Ther.

(2003)

T. Rich et al.

Defying death after DNA damage

Nature

(2000)

S. Vamvakas et al.

On the role of DNA double-strand breaks in toxicity and carcinogenesis

Crit. Rev. Toxicol.

(1997)

E.J. Hall et al.

Radiobiology for the Radiologist

(2019)

P. Tassone

BRCA1 expression modulates chemosensitivity of BRCA1-defective HCC1937 human breast cancer cells

Br. J. Cancer

(2003)

B. Evers et al.

Mouse models of BRCA1 and BRCA2 deficiency: past lessons, current understanding and future prospects

Oncogene

(2006)

N. Turner et al.

Hallmarks of’ BRCAness’ in sporadic cancers

Nat. Rev. Cancer

(2004)

X. Li et al.

Homologous recombination in DNA repair and DNA damage tolerance

Cell Res.

(2008)

R. Prakash et al.

Homologous recombination and human health: the roles of BRCA1, BRCA2, and associated proteins

Cold Spring Harb. Perspect. Biol.

(2015)

A. Kuzminov

Single-strand interruptions in replicating chromosomes cause double-strand breaks

Proc. Natl. Acad. Sci. U. S. A.

(2001)

Y. Saintigny

Characterization of homologous recombination induced by replication inhibition in mammalian cells

EMBO J.

(2001)

E. Vesela et al.

Common chemical inductors of replication stress: focus on cell-based studies

Biomolecules

(2017)

D. Strumberg

Conversion of topoisomerase I cleavage complexes on the leading strand of ribosomal DNA into 5’-phosphorylated DNA double-strand breaks by replication runoff

Mol. Cell. Biol.

(2000)

Y. Pommier et al.

Roles of eukaryotic topoisomerases in transcription, replication and genomic stability

Nat. Rev. Mol. Cell Biol.

(2016)

W. Feng et al.

Homologous recombination and replication fork protection: BRCA2 and more!

Cold Spring Harb. Symp. Quant. Biol.

(2017)

J.V. Forment et al.

Structure-specific DNA endonuclease Mus81/Eme1 generates DNA damage caused by Chk1 inactivation

PLoS One

(2011)

K. Hanada

The structure-specific endonuclease Mus81 contributes to replication restart by generating double-strand DNA breaks

Nat. Struct. Mol. Biol.

(2007)

F.B. Couch et al.

Fork reversal, too much of a good thing

Cell Cycle

(2014)

A.J. Ryan et al.

Camptothecin cytotoxicity in mammalian cells is associated with the induction of persistent double strand breaks in replicating DNA

Nucleic Acids Res.

(1991)

C.J. Lord et al.

The DNA damage response and cancer therapy

Nature

(2012)

J. Murai

Trapping of PARP1 and PARP2 by clinical PARP inhibitors

Cancer Res.

(2012)

J. Murai

Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib

Mol. Cancer Ther.

(2014)

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The joining of breaks in the DNA phosphodiester backbone is essential for genome integrity. Breaks are generated during normal processes such as DNA replication, cytosine demethylation during differentiation, gene rearrangement in the immune system and germ cell development. In addition, they are generated either directly by a DNA damaging agent or indirectly due to damage excision during repair. Breaks are joined by a DNA ligase that catalyzes phosphodiester bond formation at DNA nicks with 3′ hydroxyl and 5′ phosphate termini. Three human genes encode ATP-dependent DNA ligases. These enzymes have a conserved catalytic core consisting of three subdomains that encircle nicked duplex DNA during ligation. The DNA ligases are targeted to different nuclear DNA transactions by specific protein–protein interactions. Both DNA ligase IIIα and DNA ligase IV form stable complexes with DNA repair proteins, XRCC1 and XRCC4, respectively. There is functional redundancy between DNA ligase I and DNA ligase IIIα in DNA replication, excision repair and single-strand break repair. Although DNA ligase IV is a core component of the major double-strand break repair pathway, non-homologous end joining, the other enzymes participate in minor, alternative double-strand break repair pathways. In contrast to the nucleus, only DNA ligase IIIα is present in mitochondria and is essential for maintaining the mitochondrial genome. Human immunodeficiency syndromes caused by mutations in either LIG1 or LIG4 have been described. Preclinical studies with DNA ligase inhibitors have identified potentially targetable abnormalities in cancer cells and evidence that DNA ligases are potential targets for cancer therapy.
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The perturbation of DNA replication, a phenomena termed “replication stress”, is a driving force of genome instability and a hallmark of cancer cells. Among the DNA repair mechanisms that contribute to tolerating replication stress, the homologous recombination pathway is central to the alteration of replication fork progression. In many organisms, defects in the homologous recombination machinery result in increased cell sensitivity to replication-blocking agents and a higher risk of cancer in humans. Moreover, the status of homologous recombination in cancer cells often correlates with the efficacy of anti-cancer treatment. In this review, we discuss our current understanding of the different functions of homologous recombination in fixing replication-associated DNA damage and contributing to complete genome duplication. We also examine which functions are pivotal in preventing cancer and genome instability.
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Nuclease-independent ssDNA gaps at replication fork junctions have also been described in the absence of HR proteins bound to chromatin (Hashimoto et al., 2010; Kolinjivadi et al., 2017b). The function of HR proteins in DNA replication has been shown to be essential for cell survival and has been linked to PARP inhibitor sensitivity (Cantor, 2021; Cong and Cantor, 2022; Panzarino et al., 2021). These roles are distinct from the classical HR-mediated metabolism of DSBs, which can also be repaired through covalent joining of DNA ends by other highly efficient pathways, including classical nonhomologous end-joining (C-NHEJ) and alternative-NHEJ (alt-NHEJ) (Chang et al., 2017; Schrempf et al., 2021).
POLθ promotes repair of DNA double-strand breaks (DSBs) resulting from collapsed forks in homologous recombination (HR) defective tumors. Inactivation of POLθ results in synthetic lethality with the loss of HR genes BRCA1/2, which induces under-replicated DNA accumulation. However, it is unclear whether POLθ-dependent DNA replication prevents HR-deficiency-associated lethality. Here, we isolated Xenopus laevis POLθ and showed that it processes stalled Okazaki fragments, directly visualized by electron microscopy, thereby suppressing ssDNA gaps accumulating on lagging strands in the absence of RAD51 and preventing fork reversal. Inhibition of POLθ DNA polymerase activity leaves fork gaps unprotected, enabling their cleavage by the MRE11-NBS1-CtIP endonuclease, which produces broken forks with asymmetric single-ended DSBs, hampering BRCA2-defective cell survival. These results reveal a POLθ-dependent genome protection function preventing stalled forks rupture and highlight possible resistance mechanisms to POLθ inhibitors.
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To identify and predict tumors that will be sensitive to PARPi, much effort has been applied to scoring HRD tumors by mutational signatures, protein expression, and/or genome scaring events (van Wijk et al., 2022). The emergence of chemotherapy resistance in BRCA-deficient cancer cells also often correlated with restoration of HR and/or FP, furthering the model that a DSB is the sensitizing lesion (Cantor, 2021). Here, we diverge and propose instead that the common vulnerability of cancer cells sensitive to PARPi is aberrant ssDNA gap formation occurring in the wake of DNA replication (also called daughter-strand gaps) (Wong et al., 2021).
Defects in DNA double-strand break repair are thought to render BRCA1 or BRCA2 (BRCA) mutant tumors selectively sensitive to PARP inhibitors (PARPis). Challenging this framework, BRCA and PARP1 share functions in DNA synthesis on the lagging strand. Thus, BRCA deficiency or “BRCAness” could reflect an inherent lagging strand problem that is vulnerable to drugs such as PARPi that also target the lagging strand, a combination that generates a toxic accumulation of replication gaps.

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^☆: This Special Issue is edited by P. A. Jeggo.

^☆☆: This article is part of the special issue Cutting Edge Perspectives in Genome Maintenance VIII.

View full text

Revisiting the BRCA-pathway through the lens of replication gap suppression: “Gaps determine therapy response in BRCA mutant cancer”☆,☆☆

Abstract

Section snippets

Overview, taking on the DSB dogma

Genotoxic chemotherapy generates a range of lesions, but the DSB is considered the most toxic one

BRCA deficiency is a model of chemotherapy sensitivity and is defective in DNA repair

Could something else confer chemotherapy response?

BRCA deficient cancer cells have defects in replication gap suppression (RGS)

When BRCA deficient cancer gain resistance, RGS is also restored

Gaps are distinct from degraded forks

RGS is uniquely coupled to chemotherapy response

Cancer therapies generate lots of ssDNA

Are DSBs relevant to the response to genotoxic agents?

Is ssDNA toxic?

Declaration of Competing Interest

Acknowledgments

DNA Repair (Amst)

Mol. Cell

Curr. Probl. Cancer

DNA Repair (Amst)

Cell

Mol. Cell

Trends Mol. Med.

Mol. Oncol.

Cell

Cancer Cell

Mol. Cell

Mol. Cell

Cell Rep.

Cell

Mol. Cell

DNA Repair (Amst)

Mol. Cell

DNA Repair (Amst)

DNA Repair (Amst)

DNA double-strand breaks: signaling, repair and the cancer connection

Nat. Genet.

The DNA-damage response in human biology and disease

Nature

DNA double-strand break repair as determinant of cellular radiosensitivity to killing and target in radiation therapy

Front. Oncol.

The role of DNA single- and double-strand breaks in cell killing by ionizing radiation

Radiat. Res.

Initiation of homologous recombination at DNA nicks

Nucleic Acids Res.

Neocarzinostatin-mediated DNA damage and repair in wild-type and repair-deficient Chinese hamster ovary cells

Cancer Res.

Numerical analysis of etoposide induced DNA breaks

PLoS One

Methyl methanesulfonate (MMS) produces heat-labile DNA damage but no detectable in vivo DNA double-strand breaks

Nucleic Acids Res.

Double-strand breaks: signaling pathways and repair mechanisms

Cell. Mol. Life Sci.

Histone H2AX in DNA damage and repair

Cancer Biol. Ther.

Defying death after DNA damage

Nature

On the role of DNA double-strand breaks in toxicity and carcinogenesis

Crit. Rev. Toxicol.

Radiobiology for the Radiologist

BRCA1 expression modulates chemosensitivity of BRCA1-defective HCC1937 human breast cancer cells

Br. J. Cancer

Mouse models of BRCA1 and BRCA2 deficiency: past lessons, current understanding and future prospects

Oncogene

Hallmarks of’ BRCAness’ in sporadic cancers

Nat. Rev. Cancer

Homologous recombination in DNA repair and DNA damage tolerance

Cell Res.

Homologous recombination and human health: the roles of BRCA1, BRCA2, and associated proteins

Cold Spring Harb. Perspect. Biol.

Single-strand interruptions in replicating chromosomes cause double-strand breaks

Proc. Natl. Acad. Sci. U. S. A.

Characterization of homologous recombination induced by replication inhibition in mammalian cells

EMBO J.

Common chemical inductors of replication stress: focus on cell-based studies

Biomolecules

Conversion of topoisomerase I cleavage complexes on the leading strand of ribosomal DNA into 5’-phosphorylated DNA double-strand breaks by replication runoff

Mol. Cell. Biol.

Roles of eukaryotic topoisomerases in transcription, replication and genomic stability

Nat. Rev. Mol. Cell Biol.