CHD1L maintains genome integrity by facilitating okazaki fragment maturation

The dynamic synthesis and removal of poly (ADP-ribose) (pADPr) by poly (ADP-ribose) polymerase 1 and poly (ADP-ribose) glycohydrolase (PARG), respectively, is essential for the maintenance of genome integrity, particularly during DNA replication. However, the precise role of the pADPr-binding chromatin remodeler chromodomain helicase DNA binding protein 1-like (CHD1L) in resolving endogenous DNA damage remains unclear. Here, we identified CHD1L as a critical modulator of Okazaki fragment maturation. We demonstrated that CHD1L loss was synthetic lethal with severe inhibition of PARG. This synthetic lethality stemmed from the toxic accumulation of pADPr specifically in S-phase cells, originating from unprocessed Okazaki fragment intermediates. Rescue experiments confirmed that both the ATPase and pADPr-binding macrodomain of CHD1L were indispensable for preventing this toxic accumulation. Mechanistically, quantitative chromatin proteomics revealed that CHD1L deficiency caused the persistent and aberrant retention of single-strand break (SSB) repair factors and others including the E3 ubiquitin ligases RNF114 and DTX3L/PARP9, challenging the previous models that CHD1L loss would limit chromatin accessibility of DNA repair factors. These findings establish a novel housekeeping function for CHD1L in facilitating the efficient turnover of DNA repair factors at replication-associated SSBs.