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      The Fanconi Anemia DNA Repair Pathway: Structural and Functional Insights into a Complex Disorder

      Author(s): 1 , 2 , 3
      Publication date Created:
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      Journal: Annual Review of Biophysics
      Publisher: Annual Reviews

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          Abstract

          Mutations in any of at least sixteen FANC genes (FANCA-Q) cause Fanconi anemia, a disorder characterized by sensitivity to DNA interstrand crosslinking agents. The clinical features of cytopenia, developmental defects, and tumor predisposition are similar in each group, suggesting that the gene products participate in a common pathway. The Fanconi anemia DNA repair pathway consists of an anchor complex that recognizes damage caused by interstrand crosslinks, a multisubunit ubiquitin ligase that monoubiquitinates two substrates, and several downstream repair proteins including nucleases and homologous recombination enzymes. We review progress in the use of structural and biochemical approaches to understanding how each FANC protein functions in this pathway.

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          RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO.

          Carsten Hoege, Boris Pfander, George-Lucian Moldovan … (2002)
          The RAD6 pathway is central to post-replicative DNA repair in eukaryotic cells; however, the machinery and its regulation remain poorly understood. Two principal elements of this pathway are the ubiquitin-conjugating enzymes RAD6 and the MMS2-UBC13 heterodimer, which are recruited to chromatin by the RING-finger proteins RAD18 and RAD5, respectively. Here we show that UBC9, a small ubiquitin-related modifier (SUMO)-conjugating enzyme, is also affiliated with this pathway and that proliferating cell nuclear antigen (PCNA) -- a DNA-polymerase sliding clamp involved in DNA synthesis and repair -- is a substrate. PCNA is mono-ubiquitinated through RAD6 and RAD18, modified by lysine-63-linked multi-ubiquitination--which additionally requires MMS2, UBC13 and RAD5--and is conjugated to SUMO by UBC9. All three modifications affect the same lysine residue of PCNA, suggesting that they label PCNA for alternative functions. We demonstrate that these modifications differentially affect resistance to DNA damage, and that damage-induced PCNA ubiquitination is elementary for DNA repair and occurs at the same conserved residue in yeast and humans.
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            Y-family DNA polymerases and their role in tolerance of cellular DNA damage.

            Julian E. Sale, Alan Lehmann, Roger Woodgate (2012)
            The past 15 years have seen an explosion in our understanding of how cells replicate damaged DNA and how this can lead to mutagenesis. The Y-family DNA polymerases lie at the heart of this process, which is commonly known as translesion synthesis. This family of polymerases has unique features that enable them to synthesize DNA past damaged bases. However, as they exhibit low fidelity when copying undamaged DNA, it is essential that they are only called into play when they are absolutely required. Several layers of regulation ensure that this is achieved.
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              Biallelic inactivation of BRCA2 in Fanconi anemia.

              Niall G. Howlett, Toshiyasu Taniguchi, Susan C Olson … (2002)
              Fanconi anemia (FA) is a rare autosomal recessive cancer susceptibility disorder characterized by cellular hypersensitivity to mitomycin C (MMC). Six FA genes have been cloned, but the gene or genes corresponding to FA subtypes B and D1 remain unidentified. Here we show that cell lines derived from FA-B and FA-D1 patients have biallelic mutations in BRCA2 and express truncated BRCA2 proteins. Functional complementation of FA-D1 fibroblasts with wild-type BRCA2 complementary DNA restores MMC resistance. Our results link the six cloned FA genes with BRCA1 and BRCA2 in a common pathway. Germ-line mutation of genes in this pathway may result in cancer risks similar to those observed in families with BRCA1 or BRCA2 mutations.
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                Author and article information

                Journal
                Title: Annual Review of Biophysics
                Abbreviated Title: Annu. Rev. Biophys.
                Publisher: Annual Reviews
                ISSN (Print): 1936-122X
                ISSN (Electronic): 1936-1238
                Publication date Created: May 06 2014
                Publication date (Print): May 06 2014
                Volume: 43
                Issue: 1
                Pages: 257-278
                Affiliations
                [1 ]MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom; email:
                [2 ]Genome Stability Unit, St Vincent's Institute, Fitzroy, VIC 3065, Australia
                [3 ]Department of Medicine, The University of Melbourne, Parkville, VIC 3010 Australia; email:
                Article
                DOI: 10.1146/annurev-biophys-051013-022737
                PubMed ID: 24773018
                SO-VID: de6eb7a0-68b7-4881-a7a0-3606e145bbde
                Copyright © © 2014
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