TY - JOUR
T1 - RIF1 promotes replication fork protection and efficient restart to maintain genome stability
AU - Mukherjee, Chirantani
AU - Tripathi, Vivek
AU - Manolika, Eleni Maria
AU - Heijink, Anne Margriet
AU - Ricci, Giulia
AU - Merzouk, Sarra
AU - de Boer, H. Rudolf
AU - Demmers, Jeroen
AU - van Vugt, Marcel A. T. M.
AU - Chaudhuri, Arnab Ray
PY - 2019/7/23
Y1 - 2019/7/23
N2 - Homologous recombination (HR) and Fanconi Anemia (FA) pathway proteins in addition to their DNA repair functions, limit nuclease-mediated processing of stalled replication forks. However, the mechanism by which replication fork degradation results in genome instability is poorly understood. Here, we identify RIF1, a non-homologous end joining (NHEJ) factor, to be enriched at stalled replication forks. Rif1 knockout cells are proficient for recombination, but displayed degradation of reversed forks, which depends on DNA2 nuclease activity. Notably, RIF1-mediated protection of replication forks is independent of its function in NHEJ, but depends on its interaction with Protein Phosphatase 1. RIF1 deficiency delays fork restart and results in exposure of under-replicated DNA, which is the precursor of subsequent genomic instability. Our data implicate RIF1 to be an essential factor for replication fork protection, and uncover the mechanisms by which unprotected DNA replication forks can lead to genome instability in recombination-proficient conditions.
AB - Homologous recombination (HR) and Fanconi Anemia (FA) pathway proteins in addition to their DNA repair functions, limit nuclease-mediated processing of stalled replication forks. However, the mechanism by which replication fork degradation results in genome instability is poorly understood. Here, we identify RIF1, a non-homologous end joining (NHEJ) factor, to be enriched at stalled replication forks. Rif1 knockout cells are proficient for recombination, but displayed degradation of reversed forks, which depends on DNA2 nuclease activity. Notably, RIF1-mediated protection of replication forks is independent of its function in NHEJ, but depends on its interaction with Protein Phosphatase 1. RIF1 deficiency delays fork restart and results in exposure of under-replicated DNA, which is the precursor of subsequent genomic instability. Our data implicate RIF1 to be an essential factor for replication fork protection, and uncover the mechanisms by which unprotected DNA replication forks can lead to genome instability in recombination-proficient conditions.
KW - HOMOLOGOUS RECOMBINATION
KW - END RESECTION
KW - DNA
KW - REVERSAL
KW - REPAIR
KW - STRESS
KW - 53BP1
KW - DEGRADATION
KW - CELLS
KW - BREAK
U2 - 10.1038/s41467-019-11246-1
DO - 10.1038/s41467-019-11246-1
M3 - Article
C2 - 31337767
SN - 2041-1723
VL - 10
SP - 3287
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3287
ER -