DNA end resection

DNA end resection, also called 5′–3′ degradation, is a biochemical process where the blunt end of a section of double-stranded DNA is modified by cutting away some nucleotides from the 5' end to produce a 3' single-stranded sequence.[1][2] It is an important part of the repair mechanism of double-stranded breaks (DSB) of the DNA molecule: two of the three main mechanisms for repair of DSBs, microhomology-mediated end joining (MMEJ) and homologous recombination (HRR) rely on end resection.[3] The presence of a section of single-stranded DNA (ssDNA) allows the broken end of the DNA to line up accurately with a matching sequence, so that it can be accurately repaired.[2]

Background

A double-strand break is a kind of DNA damage in which both strands in the double helix are severed. They are particularly dangerous, because they can lead to genome rearrangements. Cases where the two strands are linked at the point of the double-strand break are even worse, because then the cell will not be able to complete mitosis when it next divides, and will either die or, in rare cases, undergo a mutation.[4][5] Three mechanisms exist to repair double-strand breaks (DSBs): non-homologous end joining (NHEJ), MMEJ, and HRR.[6][7] Of these, only NHEJ does not rely on end resection.[1]

Resection ensures that DSBs are not repaired by NHEJ (which joins broken DNA ends together without ensuring that they match), but rather by methods based on homology (matching DNA sequences). Because homologous recombination needs an intact copy of the DNA sequence (a sister chromatid) to be readily available, it can only take place during the S and G2 phases of the cell cycle. This control is exerted by cyclin-dependent kinases, which phosphorylate parts of the resection machinery.[8]

Mechanism

Before resection can take place, the break needs to be detected. In animals, this detection is done by PARP1;[9] similar systems exist in other eukaryotes: in plants, PARP2 seems to play this role.[10] PARP binding then recruits the MRN complex to the breakage site.[11] This is a highly conserved complex consisting of Mre11, Rad50 and NBS1 (known as Nibrin[12] in mammals, or Xrs2 in yeast, where this complex is called the MRX complex).

Before resection can start, CtBP1-interacting protein (CtIP) needs to bind to the MRN complex so that the first phase of resection can begin, namely short-range end resection. After phosphorylated CtIP binds, the Mre11 subunit is able to cut the 5'-terminated strand endonucleolytically, probably about 300 base pairs from the end,[13][8] and then acts as a 3'→5' exonuclease to strip away the end of the 5' strand.[13]

After this short-range resection, other protein complexes can bind, namely the long-range resection machinery, which uses 5'→3' exonuclease activity to extend the single-stranded DNA region.[8]

Like all single-stranded DNA in the nucleus, the resected region is first coated by Replication protein A (RPA) complex,[14]p235[8] but RPA is then replaced with RAD51 to form a nucleoprotein filament which can take part in the search for a matching region, allowing HRR to take place.[8]

References
  1. Liu, Ting; Huang, Jun (June 2016). "DNA End Resection: Facts and Mechanisms". Genomics, Proteomics & Bioinformatics. 14 (3): 126–130. doi:10.1016/j.gpb.2016.05.002. PMC 4936662. PMID 27240470.
  2. Donev, Rossen, ed. (2019). DNA repair (First ed.). Cambridge, MA, United States: Academic Press. p. 106. ISBN 978-0-12-815560-8. OCLC 1088407327.
  3. Huertas, Pablo (January 2010). "DNA resection in eukaryotes: deciding how to fix the break". Nature Structural & Molecular Biology. 17 (1): 11–16. doi:10.1038/nsmb.1710. ISSN 1545-9993. PMC 2850169. PMID 20051983.
  4. Acharya PV (1971). "The isolation and partial characterization of age-correlated oligo-deoxyribo-ribonucleotides with covalently linked aspartyl-glutamyl polypeptides". Johns Hopkins Medical Journal. Supplement (1): 254–60. PMID 5055816.
  5. Bjorksten J, Acharya PV, Ashman S, Wetlaufer DB (July 1971). "Gerogenic fractions in the tritiated rat". Journal of the American Geriatrics Society. 19 (7): 561–74. doi:10.1111/j.1532-5415.1971.tb02577.x. PMID 5106728.
  6. Watson JD, Baker TA, Bell SP, Gann A, Levine M, Losick R (2004). Molecular Biology of the Gene (5th ed.). Pearson Benjamin Cummings; CSHL Press. Ch. 9, 10. OCLC 936762772.
  7. Liang L, Deng L, Chen Y, Li GC, Shao C, Tischfield JA (September 2005). "Modulation of DNA end joining by nuclear proteins". The Journal of Biological Chemistry. 280 (36): 31442–49. doi:10.1074/jbc.M503776200. PMID 16012167.
  8. Casari, Erika; Rinaldi, Carlo; Marsella, Antonio; Gnugnoli, Marco; Colombo, Chiara Vittoria; Bonetti, Diego; Longhese, Maria Pia (2019-06-07). "Processing of DNA Double-Strand Breaks by the MRX Complex in a Chromatin Context". Frontiers in Molecular Biosciences. 6: 43. doi:10.3389/fmolb.2019.00043. ISSN 2296-889X. PMC 6567933. PMID 31231660.
  9. Ray Chaudhuri, Arnab; Nussenzweig, André (October 2017). "The multifaceted roles of PARP1 in DNA repair and chromatin remodelling". Nature Reviews. Molecular Cell Biology. 18 (10): 610–621. doi:10.1038/nrm.2017.53. ISSN 1471-0072. PMC 6591728. PMID 28676700.
  10. Song, Junqi; Keppler, Brian D.; Wise, Robert R.; Bent, Andrew F. (2015-05-07). McDowell, John M. (ed.). "PARP2 Is the Predominant Poly(ADP-Ribose) Polymerase in Arabidopsis DNA Damage and Immune Responses". PLOS Genetics. 11 (5): e1005200. doi:10.1371/journal.pgen.1005200. ISSN 1553-7404. PMC 4423837. PMID 25950582.
  11. Haince, Jean-François; McDonald, Darin; Rodrigue, Amélie; Déry, Ugo; Masson, Jean-Yves; Hendzel, Michael J.; Poirier, Guy G. (2008-01-11). "PARP1-dependent Kinetics of Recruitment of MRE11 and NBS1 Proteins to Multiple DNA Damage Sites". Journal of Biological Chemistry. 283 (2): 1197–1208. doi:10.1074/jbc.M706734200. ISSN 0021-9258. PMID 18025084. S2CID 6914911.
  12. "Atlas of Genetics and Cytogenetics in Oncology and Haematology - NBS1". Retrieved 2008-02-12.
  13. Mechanisms of DNA Recombination and Genome Rearrangements: Methods to Study Homologous Recombination. Academic Press. 2018-02-17. ISBN 978-0-12-814430-5.
  14. New research directions in DNA repair. Chen, Clark. Croatia: InTech. 2013. ISBN 978-953-51-1114-6. OCLC 957280914.CS1 maint: others (link)
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