DNA damage tolerance pathway involving DNA polymerase ι and the tumor suppressor p53 regulates DNA replication fork progression.

Abstract

DNA damage tolerance facilitates the progression of replication forks that have encountered obstacles on the template strands. It involves either translesion DNA synthesis initiated by proliferating cell nuclear antigen monoubiquitination or less well-characterized fork reversal and template switch mechanisms. Herein, we characterize a novel tolerance pathway requiring the tumor suppressor p53, the translesion polymerase ι (POLι), the ubiquitin ligase Rad5-related helicase-like transcription factor (HLTF), and the SWI/SNF catalytic subunit (SNF2) translocase zinc finger ran-binding domain containing 3 (ZRANB3). This novel p53 activity is lost in the exonuclease-deficient but transcriptionally active p53(H115N) mutant. Wild-type p53, but not p53(H115N), associates with POLι in vivo. Strikingly, the concerted action of p53 and POLι decelerates nascent DNA elongation and promotes HLTF/ZRANB3-dependent recombination during unperturbed DNA replication. Particularly after cross-linker-induced replication stress, p53 and POLι also act together to promote meiotic recombination enzyme 11 (MRE11)-dependent accumulation of (phospho-)replication protein A (RPA)-coated ssDNA. These results implicate a direct role of p53 in the processing of replication forks encountering obstacles on the template strand. Our findings define an unprecedented function of p53 and POLι in the DNA damage response to endogenous or exogenous replication stress.

• Authors: Stephanie Hampp, Tina Kiessling, Kerstin Buechle, Sabrina F Mansilla, Jürgen Thomale, Melanie Rall, Jinwoo Ahn, Helmut Pospiech, Vanesa Gottifredi, Lisa Wiesmüller
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 113 Issue 30 Pg. E4311-9 (07 26 2016) ISSN: 1091-6490 [Electronic] United States
• PMID: 27407148 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• HLTF protein, human
• Replication Protein A
• Transcription Factors
• Tumor Suppressor Protein p53
• DNA
• DNA-Directed DNA Polymerase
• DNA Helicases
• ZRANB3 protein, human
• DNA Polymerase iota
• POLI protein, human

Topics

• Cell Line, Tumor
• Cells, Cultured
• DNA (chemistry, genetics, metabolism)
• DNA Damage
• DNA Helicases (genetics, metabolism)
• DNA Repair
• DNA Replication
• DNA-Binding Proteins (genetics, metabolism)
• DNA-Directed DNA Polymerase (genetics, metabolism)
• Homologous Recombination
• Humans
• K562 Cells
• Nucleic Acid Conformation
• RNA Interference
• Replication Protein A (genetics, metabolism)
• Transcription Factors (genetics, metabolism)
• Tumor Suppressor Protein p53 (genetics, metabolism)
• DNA Polymerase iota