Cockayne syndrome group B protein uses its DNA translocase activity to promote mitotic DNA synthesis.

Abstract

Mitotic DNA synthesis, also known as MiDAS, has been suggested to be a form of RAD52-dependent break-induced replication (BIR) that repairs under-replicated DNA regions of the genome in mitosis prior to chromosome segregation. Cockayne syndrome group B (CSB) protein, a chromatin remodeler of the SNF2 family, has been implicated in RAD52-dependent BIR repair of stalled replication forks. However, whether CSB plays a role in MiDAS has not been characterized. Here, we report that CSB functions epistatically with RAD52 to promote MiDAS at common fragile sites in response to replication stress, and prevents genomic instability associated with defects in MiDAS. We show that CSB is dependent upon the conserved phenylalanine at position 796 (F796), which lies in the recently-reported pulling pin that is required for CSB's translocase activity, to mediate MiDAS, suggesting that CSB uses its DNA translocase activity to promote MiDAS. Structural analysis reveals that CSB shares with a subset of SNF2 family proteins a translocase regulatory region (TRR), which is important for CSB's function in MiDAS. We further demonstrate that phosphorylation of S1013 in the TRR regulates the function of CSB in MiDAS and restart of stalled forks but not in fork degradation in BRCA2-deficient cells and UV repair. Taken together, these results suggest that the DNA translocase activity of CSB in vivo is likely to be highly regulated by post-translational modification in a context-specific manner.

• Authors: Shixin Cui, John R Walker, Nicole L Batenburg, Xu-Dong Zhu
• Journal: DNA repair (DNA Repair (Amst)) Vol. 116 Pg. 103354 (08 2022) ISSN: 1568-7856 [Electronic] Netherlands
• PMID: 35738143 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier B.V. All rights reserved.

Chemical References

• Chromatin
• Poly-ADP-Ribose Binding Proteins
• DNA
• DNA Repair Enzymes

Topics

• Chromatin
• Cockayne Syndrome (genetics)
• DNA (metabolism)
• DNA Repair
• DNA Repair Enzymes (metabolism)
• DNA Replication
• Humans
• Poly-ADP-Ribose Binding Proteins (metabolism)