Hypersensitivity to DNA double‐strand breaks associated with PARG deficiency is suppressed by exo‐1 and polq‐1 mutations in Caenorhabditis elegans
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...
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Veröffentlicht in: | The FEBS journal 2020-03, Vol.287 (6), p.1101-1115 |
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Zusammenfassung: | 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.
DNA breaks cause the recruitment of proteins that mediate DNA repair and activation of the DNA checkpoint; among those are poly(ADP‐ribose) polymerases (PARPs) for poly(ADP‐ribosyl)ation and protein modifications and the less‐well understood PAR glycohydrolases (PARGs). Here, Hyeon‐Sook Koo and colleagues investigate the relationship between PARGs and DNA double‐strand breaks (DSBs) in Caenorhabditis elegans and found that PARG‐2 prevents excessive end resection at DSBs by suppressing the overexpression of exonuclease‐1 mRNA. In the absence of PARG‐2, the hyperactive end resection at DSBs lowers the efficiency of homologous recombination (HR) and diverts DNA intermediates to the alternative end‐joining (Alt‐EJ) pathway. |
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ISSN: | 1742-464X 1742-4658 |
DOI: | 10.1111/febs.15082 |