Self-reversal facilitates the resolution of HMCES DNA-protein crosslinks in cells
Year: 2023
Type: article
Abstract: Abasic sites are common DNA lesions that stall polymerases and threaten genome stability. When located in single-stranded DNA (ssDNA), they are shielded from aberrant processing by HMCES via a DNA-protein crosslink (DPC) that prevents double-strand breaks. Nevertheless, the HMCES-DPC must be removed to complete DNA repair. Here, we found that DNA polymerase α inhibition generates ssDNA abasic sites and HMCES-DPCs. These DPCs are resolved with a half-life of approximately 1.5 hours. Resolution does not require the proteasome or SPRTN protease. Instead, HMCES-DPC self-reversal is important for resolution. Biochemically, self-reversal is favored when the ssDNA is converted to duplex DNA. When the self-reversal mechanism is inactivated, HMCES-DPC removal is delayed, cell proliferation is slowed, and cells become hypersensitive to DNA damage agents that increase AP site formation. Thus, HMCES-DPC formation followed by self-reversal is an important mechanism for ssDNA AP site management.
Source: Cell Reports
Institutions: Vanderbilt University, Vanderbilt University Medical Center
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,460
Funders: Vanderbilt University, Vanderbilt-Ingram Cancer Center, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Environmental Health Sciences, Vanderbilt Institute of Chemical Biology, School of Medicine, Vanderbilt University
Awards: G1300984159, The molecular basis of SRAP domain DNA-protein crosslinking, The mutagenic consequences of replication-coupled DNA repair mechanisms, G899959004, Cancer Center Support Grant, The DNA replication-repair interface: mechanisms and regulation, Function of HMCES in abasic site repair and tolerance, The mutagenic consequences of replication-coupled DNA repair mechanisms
OpenAlex ID: W4388583260