Liu W, Krishnamoorthy A, Zhao R, Cortez D
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37237, USA.
Sci Adv. 2020 Nov 13;6(46). doi: 10.1126/sciadv.abc3598. Print 2020 Nov.
Fork reversal is a common response to replication stress, but it generates a DNA end that is susceptible to degradation. Many fork protection factors block degradation, but how they work remains unclear. Here, we find that 53BP1 protects forks from DNA2-mediated degradation in a cell type-specific manner. Fork protection by 53BP1 reduces S-phase DNA damage and hypersensitivity to replication stress. Unlike BRCA2, FANCD2, and ABRO1 that protect reversed forks generated by SMARCAL1, ZRANB3, and HLTF, 53BP1 protects forks remodeled by FBH1. This property is shared by the fork protection factors FANCA, FANCC, FANCG, BOD1L, and VHL. RAD51 is required to generate the resection substrate in all cases. Unexpectedly, BRCA2 is also required for fork degradation in the FBH1 pathway or when RAD51 activity is partially compromised. We conclude that there are multiple fork protection mechanisms that operate downstream of at least two RAD51-dependent fork remodeling pathways.
叉形结构逆转是对复制应激的常见反应，但它会产生易降解的DNA末端。许多叉形保护因子可阻止降解，但其作用机制尚不清楚。在此，我们发现53BP1以细胞类型特异性方式保护叉形结构免受DNA2介导的降解。53BP1对叉形结构的保护可减少S期DNA损伤以及对复制应激的超敏反应。与保护由SMARCAL1、ZRANB3和HLTF产生的逆转叉形结构的BRCA2、FANCD2和ABRO1不同，53BP1保护由FBH1重塑的叉形结构。叉形保护因子FANCA、FANCC、FANCG、BOD1L和VHL也具有此特性。在所有情况下，生成切除底物都需要RAD51。出乎意料的是，在FBH1途径中或当RAD51活性部分受损时，叉形结构降解也需要BRCA2。我们得出结论，至少在两条依赖RAD51的叉形重塑途径下游存在多种叉形保护机制。
