Abstract
Human HLTF participates in the lesion-bypass mechanism through the fork reversal structure, known as template switching of post-replication repair. However, the mechanism by which HLTF promotes the replication progression and fork stability of damaged forks remains unclear. Here, we identify a novel protein–protein interaction between HLTF and PARP1. The depletion of HLTF and PARP1 increases chromosome breaks, further reduces the length of replication tracks, and concomitantly increases the number of stalled forks after methyl methanesulfonate treatment according to a DNA fiber analysis. The progression of replication also depends on BARD1 in the presence of MMS treatment. By combining 5-ethynyl-2′-deoxyuridine with a proximity ligation assay, we revealed that the HLTF, PARP1, and BRCA1/BARD1/RAD51 proteins were initially recruited to damaged forks. However, prolonged stalling of damaged forks results in fork collapse. HLTF and PCNA dissociate from the collapsed forks, with increased accumulation of PARP1 and BRCA1/BARD1/RAD51 at the collapsed forks. Our results reveal that HLTF together with PARP1 and BARD1 participates in the stabilization of damaged forks, and the PARP1–BARD1 interaction is further involved in the repair of collapse forks.
Highlights
Despite the fact that cells have evolved several DNA repair mechanisms to repair DNA damage, it is almost inevitable that some DNA lesions will escape these repair mechanisms and collide with active replication forks
We identify a novel protein–protein interaction between HLTF and PARP1
In this study, we identify a novel protein–protein interaction between HLTF and PARP1
Summary
Despite the fact that cells have evolved several DNA repair mechanisms to repair DNA damage, it is almost inevitable that some DNA lesions will escape these repair mechanisms and collide with active replication forks. In prokaryotic cells, stalled or collapsed replication forks are reactivated by recombination-dependent pathways[3]. In addition to HLTF, SMARCAL1 and ZRANB3 are able to convert stalled forks into reversed forks[21,22,23,24], and the formation of reversed forks depends on RAD51 recombinase[19,20]. It remains unclear whether these helicases work together, act alone, or depend on the types of DNA lesions
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