Abstract
RNF168 promotes chromosomal break localization of 53BP1 and BRCA1; 53BP1 loss rescues homologous recombination (HR) in BRCA1-deficient cells. RNF168 depletion suppresses HR defects caused by BRCA1 silencing; RNF168 influences HR similarly to 53BP1. RNF168 is important for HR defects caused by BRCA1 loss. Although RNF168 promotes BRCA1 and 53BP1 localization to chromosomal breaks, RNF168 affects HR similarly to 53BP1. The RING finger nuclear factor RNF168 is required for recruitment of several DNA damage response factors to double strand breaks (DSBs), including 53BP1 and BRCA1. Because 53BP1 and BRCA1 function antagonistically during the DSB repair pathway homologous recombination (HR), the influence of RNF168 on HR has been unclear. We report that RNF168 depletion causes an elevated frequency of two distinct HR pathways (homology-directed repair and single strand annealing), suppresses defects in HR caused by BRCA1 silencing, but does not suppress HR defects caused by disruption of CtIP, RAD50, BRCA2, or RAD51. Furthermore, RNF168-depleted cells can form ionizing radiation-induced foci of the recombinase RAD51 without forming BRCA1 ionizing radiation-induced foci, indicating that this loss of BRCA1 recruitment to DSBs does not reflect a loss of function during HR. Additionally, we find that RNF168 and 53BP1 have a similar influence on HR. We suggest that RNF168 is important for HR defects caused by BRCA1 loss.
Highlights
RNF168 promotes chromosomal break localization of 53BP1 and BRCA1; 53BP1 loss rescues homologous recombination (HR) in BRCA1-deficient cells
We report that RNF168 depletion causes an elevated frequency of two distinct HR pathways, suppresses defects in HR caused by BRCA1 silencing, but does not suppress HR defects caused by disruption of CtIP, RAD50, BRCA2, or RAD51
We suggest that RNF168 is important for HR defects caused by BRCA1 loss
Summary
RNF168 promotes chromosomal break localization of 53BP1 and BRCA1; 53BP1 loss rescues homologous recombination (HR) in BRCA1-deficient cells. RNF168 is an E3 ubiquitin ligase that is critical for IRIF of several downstream DNA damage response proteins, which notably includes both 53BP1 and the breast and ovarian cancer susceptibility factor BRCA1 [1, 3, 4] These two DNA damage response factors appear to act antagonistically during DSB repair by homologous recombination (HR), in that the loss of 53BP1 can rescue HR in BRCA1-deficient cells [5, 6]. BRCA1 promotes both HDR and SSA [9] and has been postulated to promote end processing during HR [14], the precise function of BRCA1 during HR homologous recombination; IR, ionizing radiation; IRIF, ionizing radiationinduced foci; PICH, Plk1-interacting checkpoint helicase; siCTRL, nontargeting siRNA; SSA, single strand annealing; E3, ubiquitin-protein isopeptide ligase; RPA, replication protein A. These findings indicate that RNF168 is important for HR defects caused by BRCA1 silencing
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