Ectopic expression of RNF168 and 53BP1 increases mutagenic but not physiological non-homologous end joining
Authors: Jiri Lukas
André Nussenzweig
Dali Zong
Claudia Lukas
Elsa Callén
Gianluca Pegoraro
Journal: Nucleic Acids Research (2015)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: DNA double strand breaks; homologous recombination; non-homologous end joining; 53BP1; BRCA1
Affiliations: Laboratory of Genome Integrity; National Cancer Institute; National Institutes of Health; Bethesda, MD 20892, USA., Center for Cancer Research, National Cancer Institute; National Institute of Health, Bethesda, MD 20892, USA., The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Faculty of Health and Medical Sciences, Blegdamsvej 3, 2200, Copenhagen, Denmark., Laboratory of Genome Integrity; National Cancer Institute; National Institutes of Health; Bethesda, MD 20892, USA .

Abstract:  DNA double strand breaks (DSBs) formed during S phase are preferentially repaired by homologous recombination (HR), whereas G1 DSBs, such as those occurring during immunoglobulin class switch recombination (CSR), are repaired by non-homologous end joining (NHEJ). The DNA damage response proteins 53BP1 and BRCA1 regulate the balance between NHEJ and HR. 53BP1 promotes CSR in part by mediating synapsis of distal DNA ends, and in addition, inhibits 5' end resection. BRCA1 antagonizes 53BP1 dependent DNA end-blocking activity during S phase, which would otherwise promote mutagenic NHEJ and genome instability. Recently, it was shown that supra-physiological levels of the E3 ubiquitin ligase RNF168 results in the hyper-accumulation of 53BP1/BRCA1 which accelerates DSB repair. Here, we ask whether increased expression of RNF168 or 53BP1 impacts physiological versus mutagenic NHEJ. We find that the anti-resection activities of 53BP1 are rate-limiting for mutagenic NHEJ but not for physiological CSR. As heterogeneity in the expression of RNF168 and 53BP1 is found in human tumors, our results suggest that deregulation of the RNF168/53BP1 pathway could alter the chemosensitivity of BRCA1 deficient tumors. 

Retracted: No

PubPeer comments:
 Figure 4D: More similar than expected. Could authors check please? ![file] , 
 Hi Anaperus, Thank you for bring this to my attention. I agree with you that these two panels look identical. I wonder if there was an error where during figure assembly where instead of inserting the two corresponding tubular panels, one of them got inserted twice. This has never happened to me before, and if it is what happened, I m embarrassed by this mistake. Currently our server is down but I will check this as soon as possible (probably next week). sincerely, Dali , 
 Hi Anaperus, Thank you for alerting us to this error in our paper. We have now examined the original blots and determined that the Tubulin panel was indeed inadvertently duplicated during figure assembly. To ensure transparency and to correct the scientific record, we have included the original blots here and explain how the mix-up came about. We have also initiated contact with the journal regarding the issuance of an erratum, which does not change any of the conclusions. Thanks again for pointing this out. Sincerely, The authors ![file] ![file] P.S. PubPeer did not allow the attachment of files 1MB, hence we were only able to upload the images as PNG, but not in their original format. , 
 #3 Thank you for your reply. If you wish to provide a higher resolution image here, one option is to upload that image to a third party image sharing site, like [Imgur] , and post a link to that site here. , 
 2022 correction. https: academic.oup.com nar advance-article doi 10.1093 nar gkac126 6533619 In Figure 4D of the original published version, the u03b1-Tubulin panel was inadvertently duplicated during figure assembly. To ensure transparency and to correct the scientific record, the authors provide the original blots and a new Figure 4D below. This change does not affect the results, discussion and conclusions presented in the article. ,