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Genes and pathways involved in senescence bypass identified by functional genetic screens
Mechanisms of Ageing and Development ( IF 5.3 ) Pub Date : 2021-01-08 , DOI: 10.1016/j.mad.2021.111432
Eugenia Roupakia 1 , Georgios S Markopoulos 1 , Evangelos Kolettas 1
Affiliation  

Cellular senescence is a state of stable and irreversible cell cycle arrest with active metabolism, that normal cells undergo after a finite number of divisions (Hayflick limit). Senescence can be triggered by intrinsic and/or extrinsic stimuli including telomere shortening at the end of a cell’s lifespan (telomere-initiated senescence) and in response to oxidative, genotoxic or oncogenic stresses (stress-induced premature senescence). Several effector mechanisms have been proposed to explain senescence programmes in diploid cells, including the induction of DNA damage responses, a senescence-associated secretory phenotype and epigenetic changes. Senescent cells display senescence-associated-β-galactosidase activity and undergo chromatin remodeling resulting in heterochromatinisation. Senescence is established by the pRb and p53 tumour suppressor networks. Senescence has been detected in in vitro cellular settings and in premalignant, but not malignant lesions in mice and humans expressing mutant oncogenes. Despite oncogene-induced senescence, which is believed to be a cancer initiating barrier and other tumour suppressive mechanisms, benign cancers may still develop into malignancies by bypassing senescence. Here, we summarise the functional genetic screens that have identified genes, uncovered pathways and characterised mechanisms involved in senescence evasion. These include cell cycle regulators and tumour suppressor pathways, DNA damage response pathways, epigenetic regulators, SASP components and noncoding RNAs.



中文翻译:

通过功能遗传筛选鉴定的参与衰老旁路的基因和途径

细胞衰老是一种稳定且不可逆的细胞周期停滞状态,代谢活跃,正常细胞在经过有限次分裂后会经历这种状态(海弗利克极限))。衰老可以由内在和/或外在刺激触发,包括细胞寿命结束时的端粒缩短(端粒引发的衰老)和对氧化、基因毒性或致癌应激(应激诱导的过早衰老)的反应。已经提出了几种效应机制来解释二倍体细胞的衰老程序,包括 DNA 损伤反应的诱导、衰老相关的分泌表型和表观遗传变化。衰老细胞表现出衰老相关的 β-半乳糖苷酶活性,并进行染色质重塑,导致异染色质化。衰老是由 pRb 和 p53 肿瘤抑制网络建立的。已在体外检测到衰老细胞环境中以及在表达突变癌基因的小鼠和人类的癌前病变中,但不是恶性病变。尽管癌基因诱导的衰老被认为是癌症启动屏障和其他肿瘤抑制机制,但良性癌症仍可能通过绕过衰老发展为恶性肿瘤。在这里,我们总结了功能遗传筛选,这些筛选已经确定了基因、发现的途径和参与衰老逃避的表征机制。这些包括细胞周期调节因子和肿瘤抑制通路、DNA 损伤反应通路、表观遗传调节因子、SASP 成分和非编码 RNA。

更新日期:2021-01-13
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