A DNA damage tolerance pathway involving DNA polymerase iota and the tumor suppressor p53 regulates DNA replication fork progression

S HAMPP, T KIESSLINGA, K BUECHLEA, S F. MANSILLAB, J THOMALEC, M RALLA, J AHN, H POSPIECHE, V GOTTIFREDI, AND LWIESMÜLLER

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

NATL ACAD SCIENCES

Año: 2016 vol. 113 p. 4311 - 4319

0027-8424

DNA damage tolerance facilitates the progression of replicationforks that have encountered obstacles on the template strands. Itinvolves either translesion DNA synthesis initiated by proliferatingcell nuclear antigen monoubiquitination or less well-characterizedfork reversal and template switch mechanisms. Herein, we characterize a novel tolerance pathway requiring the tumor suppressorp53, the translesion polymerase ι (POLι), the RAD5-related HLTF, and the SNF2 translocase 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 POLιin vivo. Strikingly, the concerted action of p53 and POLι deceleratesnascent DNA elongation and promotes HLTF/ZRANB3-dependent recombinationduring unperturbed DNA replication. Particularly after cross-linker?induced replication stress, p53 and POLι also act together to promote MRE11-dependent accumulation of (phospho-)RPA-coated ssDNA. These results implicate a direct role of p53 in the processing of replication forks encountering obstacleson the template strand. Our findings define an unprecedented function of p53 and POLι in the DNA damage response to endogenous or exogenous replication stress.