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Hypersensitivity to DNA double-strand breaks associated with PARG deficiency is suppressed by exo-1 and polq-1 mutations in Caenorhabditis elegans.
The FEBS Journal ( IF 5.4 ) Pub Date : 2019-10-08 , DOI: 10.1111/febs.15082
Woori Bae 1 , Jae Hyung Park 1 , Myon-Hee Lee 2 , Hyun Woo Park 1 , Hyeon-Sook Koo 1
Affiliation  

Deficiency of either of the two homologs of poly(ADP-ribose) glycohydrolase (PARG), PARG-1 and PARG-2, in Caenorhabditis elegans leads to hypersensitivity to ionizing radiation (IR). In the germ cells of parg-2 mutant worms, the dissipation of recombinase RAD-51 foci was slower than in wild-type (WT) cells, suggesting defects in DNA double-strand break (DSB) repair via homologous recombination (HR). Nevertheless, RPA-1, the large subunit of replication protein A, accumulated faster in parg-2 worms and disappeared earlier than in WT worms. This accelerated RPA-1 accumulation may result from the enhanced expression of exonuclease-1 (EXO-1) after IR treatment. Accordingly, an exo-1 mutation reduced IR sensitivity and accumulation of RPA-1 in parg-2 worms. A mutation of polq-1, encoding for a key factor in the alternative end-joining (Alt-EJ) pathway, suppressed the IR hypersensitivity phenotype of parg-2 worms and normalized the kinetics of RAD-51 dissipation. This indicates that error-prone Alt-EJ may mediate DSB repair in parg-2 worms, causing hypersensitivity to IR. In summary, PARG-2 deficiency in C. elegans causes hyperactive DSB end resection likely through EXO-1 overproduction. DSBs with long single-stranded DNA ends in parg-2 worms are thought to be repaired by Alt-EJ instead of HR, causing genomic instability.

中文翻译:

秀丽隐杆线虫的exo-1和polq-1突变抑制了与PARG缺失相关的DNA双链断裂的超敏性。

秀丽隐杆线虫中两个聚(ADP-核糖)糖水解酶(PARG)PARG-1和PARG-2的同系物的缺乏导致对电离辐射(IR)过敏。在parg-2突变蠕虫的生殖细胞中,重组酶RAD-51焦点的耗散比野生型(WT)细胞慢,这表明通过同源重组(HR)修复DNA双链断裂(DSB)的缺陷。但是,RPA-1是复制蛋白A的大亚基,在parg-2蠕虫中积累得更快,并且比WT蠕虫中更早消失。加速的RPA-1积累可能是由于IR治疗后核酸外切酶1(EXO-1)表达的增强所致。因此,exo-1突变降低了parg-2蠕虫的IR敏感性和RPA-1的积累。polq-1突变,编码替代末端连接(Alt-EJ)途径中的关键因素,抑制了parg-2蠕虫的IR超敏性表型,并使RAD-51耗散动力学标准化。这表明容易出错的Alt-EJ可能介导parg-2蠕虫中的DSB修复,从而导致对IR过敏。总之,秀丽隐杆线虫中PARG-2的缺乏可能导致EXB-1过度生产而导致DSB末端过度活跃。人们认为parg-2蠕虫中具有长单链DNA末端的DSB可以通过Alt-EJ而非HR修复,从而导致基因组不稳定。
更新日期:2020-03-16
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