Corrections CELL BIOLOGY MEDICAL SCIENCES Correction for “Dysregulation of PAD4-mediated citrullination Correction for “BRCA1 promotes the ubiquitination of PCNA of nuclear GSK3β activates TGF-β signaling and induces epithelial- and recruitment of translesion polymerases in response to rep- to-mesenchymal transition in breast cancer cells,” by Sonja C. lication blockade,” by Fen Tian, Shilpy Sharma, Jianqiu Zou, Stadler, C. Theresa Vincent, Victor D. Fedorov, Antonia Patsialou, Shiaw-Yih Lin, Bin Wang, Khosrow Rezvani, Hongmin Wang, Brian D. Cherrington, Joseph J. Wakshlag, Sunish Mohanan, Barry Jeffrey D. Parvin, Thomas Ludwig, Christine E. Canman, and M. Zee, Xuesen Zhang, Benjamin A. Garcia, John S. Condeelis, Dong Zhang, which appeared in issue 33, August 13, 2013, of Anthony M. C. Brown, Scott A. Coonrod, and C. David Allis, which Proc Natl Acad Sci USA (110:13558–13563; first published July appeared in issue 29, July 16, 2013, of Proc Natl Acad Sci USA 30, 2013; 10.1073/pnas.1306534110). (110:11851–11856; first published July 1, 2013; 10.1073/pnas. The authors note that they omitted a reference to an article by 1308362110). Pathania et al. The complete reference appears below. The authors note that the affiliation for C. Theresa Vincent Furthermore, the authors note that “It is important to note should also include kCell and Developmental Biology, Weill that the role of BRCA1 in response to UV induced replication Cornell Medical College, New York, NY 10065. The corrected stress has also been examined by Livingston and colleagues (41). author and affiliation lines appear below. The online version has Both studies observed some overlapping phenotypes in BRCA1 been corrected. depleted cells (for example, the reduction of RPA foci when treated with UV). However, the two studies also have some discrep- Sonja C. Stadlera,b, C. Theresa Vincentc,d,k, Victor D. ancies with respect to PCNA ubiquitination. We speculate that Fedorove, Antonia Patsialouf, Brian D. Cherringtong, these discrepancies may be due to the knockdown efficiency BRCA1 ” Joseph J. Wakshlagh, Sunish Mohanani, Barry M. Zeej, of . Xuesen Zhangi, Benjamin A. Garciaj, John S. Condeelisf, k i Anthony M. C. Brown , Scott A. Coonrod , 41. Pathania S, et al. (2011) BRCA1 is required for postreplication repair after UV-induced and C. David Allisa DNA damage. Mol Cell 44(2):235–251. www.pnas.org/cgi/doi/10.1073/pnas.1316463110 aLaboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065; bInstitute of Laboratory Medicine, Clinical Chemistry, and Molecular Diagnostics and LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, 04103 Leipzig, Germany; Departments of cPhysiology and Biophysics and kCell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065; dDepartment of Medicine, Center for Molecular Medicine, Karolinska Institutet, 171 76 PLANT BIOLOGY Stockholm, Sweden; eCenter for Cell Engineering, Molecular Pharmacology Correction for “Dirigent domain-containing protein is part of the and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New f machinery required for formation of the lignin-based Casparian York, NY 10065; Department of Anatomy and Structural Biology, Albert ” Einstein College of Medicine, Bronx, NY 10461; gDepartment of Zoology strip in the root, by Prashant S. Hosmani, Takehiro Kamiya, and Physiology, University of Wyoming, Laramie, WY 82071; hDepartment John Danku, Sadaf Naseer, Niko Geldner, Mary Lou Guerinot, of Clinical Sciences and iBaker Institute for Animal Health, College of and David E. Salt, which appeared in issue 35, August 27, 2013, j Veterinary Medicine, Cornell University, Ithaca, NY 14853; and Department of Proc Natl Acad Sci USA (110:14498–14503; first published of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 August 12, 2013; 10.1073/pnas.1308412110). The authors note that the contributions line appeared incor- www.pnas.org/cgi/doi/10.1073/pnas.1315590110 rectly. The corrected author contributions footnote appears below. P.S.H., T.K., N.G., M.L.G., and D.E.S. designed research; P.S.H., T.K., J.D., and S.N. performed research; P.S.H., T.K., J.D., S.N., N.G., M.L.G., and D.E.S. analyzed data; and P.S.H. and D.E.S. wrote the paper. www.pnas.org/cgi/doi/10.1073/pnas.1315919110 CORRECTIONS www.pnas.org PNAS | October 1, 2013 | vol. 110 | no. 40 | 16283 Downloaded by guest on September 27, 2021 BRCA1 promotes the ubiquitination of PCNA and recruitment of translesion polymerases in response to replication blockade Fen Tiana, Shilpy Sharmab, Jianqiu Zoua, Shiaw-Yih Linc, Bin Wangd, Khosrow Rezvania, Hongmin Wanga, Jeffrey D. Parvine, Thomas Ludwigf, Christine E. Canmanb, and Dong Zhanga,1 aBasic Biomedical Science Division, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069; bDepartment of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109-2200; Departments of cSystems Biology and dGenetics, University of Texas MD Anderson Cancer Center, Houston, TX 77054; and Departments of eBiomedical Informatics and fMolecular and Cellular Biochemistry, The Ohio State University, Columbus, OH 43210 Edited* by Stephen J. Elledge, Harvard Medical School, Boston, MA, and approved July 3, 2013 (received for review April 8, 2013) Breast cancer gene 1 (BRCA1)deficient cells not only are hypersen- To date, most studies in mammalian cells on DDT have fo- sitive to double-strand breaks but also are hypersensitive to UV cused on the regulation of TLS because of the lack of robust irradiation and other agents that cause replication blockade; how- assays for template switching and the difficulty in detecting the ever, the molecular mechanisms behind these latter sensitivities polyubiquitinated form of PCNA. TLS can be either error-free are largely unknown. Here, we report that BRCA1 promotes cell or error-prone, depending on the specific lesion being bypassed survival by directly regulating the DNA damage tolerance pathway and the TLS polymerase involved in inserting nucleotides oppo- site the lesion. For example, TLS polymerase eta (Polη) can by- in response to agents that create cross-links in DNA. We show that fi BRCA1 not only promotes efficient mono- and polyubiquitination pass a thymidine dimer induced by UV with high delity (16, 17). of proliferating cell nuclear antigen (PCNA) by regulating the re- In addition to the enzymes involved in ubiquitinating PCNA, the cruitment of replication protein A, Rad18, and helicase-like tran- single-stranded DNA (ssDNA) binding protein, replication pro- tein A (RPA), is also important for the ubiquitination of PCNA scription factor to chromatin but also directly recruits translesion and functions to recruit the E3 ligase, Rad18 (12, 18). Both polymerases, such as Polymerase eta and Rev1, to the lesions through – branches of the DDT pathways appear to be more complex in protein protein interactions. Our data suggest that BRCA1 plays mammals. For example, two Saccharomyces cerevisiae Rad5 a critical role in promoting translesion DNA synthesis as well as homologs have been identified in mammals, HLTF and SHPRH DNA template switching. (19–22). Both can bind the E2 heterodimer, UBC13 and MMS2, and promote the polyubiquitination of PCNA in vitro and in NA damage response (DDR) and DNA repair are vital for vivo. Many additional regulatory factors have also been identified Dpreserving genomic integrity during a normal cell cycle and in mammalian cells that influence the DDT pathway (13, 14, 23). after genotoxic stress (1). In humans, many factors involved in Even though the core reaction and enzymes involved in DDT DDR and DNA repair, such as BRCA1 and BRCA2, are well- have been identified, the detailed mechanism of how this process known tumor suppressors. BRCA1 has been linked to both fa- is precisely regulated in mammalian cells remains unclear. Here, milial and sporadic breast and ovarian cancers, and it operates in we show that BRCA1 affects cell survival after exposure to UV, multiple biological pathways including DDR and DNA repair CDDP, and MMC by directly promoting the DDT pathway. (2, 3). BRCA1 is essential for the homologous recombination BRCA1 promotes efficient mono- and polyubiquitination of PCNA (HR) repair pathway, and therefore, cells deficient in BRCA1 by regulating the recruitment of RPA, Rad18, and HLTF to stalled function are hypersensitive to ionizing radiation and other drugs replication forks. Our data suggest that BRCA1 likely plays an that directly induce double-strand breaks (DSBs) (4). The fact that important role in both TLS and template switching. BRCA1-deficient cells are also hypersensitive to agents that form Results cis adducts on DNA or cross-link DNA, including UV, cis-platin ( - BRCA1 Promotes the Monoubiquitination of PCNA in Response to UV, diamminedichloroplatinum[II]; CDDP),and mitomycin C (MMC), CDDP, and MMC. In addition to being hypersensitive to DSBs, suggests that BRCA1 is important for other responses as well (Fig. BRCA1-deficient mammalian cells are also hypersensitive to 1 A and B)(6–8). Furthermore, Nussenzweig and coworkers re- agents that block DNA replication, including the DNA lesions cently showed that BRCA1 activity is important for resistance to created by UV, CDDP, and MMC, all of which can activate the DNA interstrand cross-links in a manner that is separable from its DDT pathways (Fig. 1 A and B)(6–8). role in HR (9). One common feature of the lesions created by UV, To investigate the potential role of BRCA1 in the DDT CDDP, and MMC is that they all have the potential to block the pathway and whether defective DDT contributes to the UV, progression of replicative DNA polymerases and activate the CDDP, and MMC hypersensitivities exhibited by BRCA1-deficient – DNA damage tolerance (DDT) pathway in mammalian cells (10 cells, we first examined the effects of BRCA1 deficiency on the 12). The DDT pathway is critical for cell viability when replication- monoubiquitination of PCNA in human cells.