| Structural highlights
Disease
[DCR1B_HUMAN] Defects in DCLRE1B may be a cause of Hoyeraal-Hreidarsson syndrome (HHS) [MIM:300240]. HHS is a multisystem disorder affecting males and is characterized by aplastic anemia, immunodeficiency, microcephaly, cerebellar hypoplasia, and growth retardation. Note=An aberrant splice variant designated Apollo-Delta has been found in a patient with Hoyeraal-Hreidarsson syndrome. Apollo-Delta hampers the proper replication of telomeres, leading to major telomeric dysfunction and cellular senescence, but maintains its DNA interstrand cross-link repair function in the whole genome.[1]
Function
[DCR1B_HUMAN] 5'-3' exonuclease that plays a central role in telomere maintenance and protection during S-phase. Participates in the protection of telomeres against non-homologous end-joining (NHEJ)-mediated repair, thereby ensuring that telomeres do not fuse. Plays a key role in telomeric loop (T loop) formation by being recruited by TERF2 at the leading end telomeres and by processing leading-end telomeres immediately after their replication via its exonuclease activity: generates 3' single-stranded overhang at the leading end telomeres avoiding blunt leading-end telomeres that are vulnerable to end-joining reactions and expose the telomere end in a manner that activates the DNA repair pathways. Together with TERF2, required to protect telomeres from replicative damage during replication by controlling the amount of DNA topoisomerase (TOP1, TOP2A and TOP2B) needed for telomere replication during fork passage and prevent aberrant telomere topology. Also involved in response to DNA damage: plays a role in response to DNA interstrand cross-links (ICLs) by facilitating double-strand break formation. In case of spindle stress, involved in prophase checkpoint.[2] [3] [4] [5] [6] [7] [8] [9] [10]
Publication Abstract from PubMed
The human SNM1A and SNM1B/Apollo proteins are members of an extended family of eukaryotic nuclease containing a motif related to the prokaryotic metallo-beta-lactamase (MBL) fold. SNM1A is a key exonuclease during replication-dependent and transcription-coupled interstrand crosslink repair, while SNM1B/Apollo is required for maintaining telomeric overhangs. Here, we report the crystal structures of SNM1A and SNM1B at 2.16 A. While both proteins contain a typical MBL-beta-CASP domain, a region of positive charge surrounds the active site of SNM1A, which is absent in SNM1B and explains the greater apparent processivity of SNM1A. The structures of both proteins also reveal a putative, wide DNA-binding groove. Extensive mutagenesis of this groove, coupled with detailed biochemical analysis, identified residues that did not impact on SNM1A catalytic activity, but drastically reduced its processivity. Moreover, we identified a key role for this groove for efficient digestion past DNA interstrand crosslinks, facilitating the key DNA repair reaction catalysed by SNM1A. Together, the architecture and dimensions of this groove, coupled to the surrounding region of high positive charge, explain the remarkable ability of SNM1A to accommodate and efficiently digest highly distorted DNA substrates, such as those containing DNA lesions.
The structures of the SNM1A and SNM1B/Apollo nuclease domains reveal a potential basis for their distinct DNA processing activities.,Allerston CK, Lee SY, Newman JA, Schofield CJ, McHugh PJ, Gileadi O Nucleic Acids Res. 2015 Dec 15;43(22):11047-60. doi: 10.1093/nar/gkv1256. Epub, 2015 Nov 17. PMID:26582912[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Touzot F, Callebaut I, Soulier J, Gaillard L, Azerrad C, Durandy A, Fischer A, de Villartay JP, Revy P. Function of Apollo (SNM1B) at telomere highlighted by a splice variant identified in a patient with Hoyeraal-Hreidarsson syndrome. Proc Natl Acad Sci U S A. 2010 Jun 1;107(22):10097-102. doi:, 10.1073/pnas.0914918107. Epub 2010 May 17. PMID:20479256 doi:10.1073/pnas.0914918107
- ↑ Ishiai M, Kimura M, Namikoshi K, Yamazoe M, Yamamoto K, Arakawa H, Agematsu K, Matsushita N, Takeda S, Buerstedde JM, Takata M. DNA cross-link repair protein SNM1A interacts with PIAS1 in nuclear focus formation. Mol Cell Biol. 2004 Dec;24(24):10733-41. PMID:15572677 doi:24/24/10733
- ↑ Demuth I, Digweed M, Concannon P. Human SNM1B is required for normal cellular response to both DNA interstrand crosslink-inducing agents and ionizing radiation. Oncogene. 2004 Nov 11;23(53):8611-8. PMID:15467758 doi:1207895
- ↑ van Overbeek M, de Lange T. Apollo, an Artemis-related nuclease, interacts with TRF2 and protects human telomeres in S phase. Curr Biol. 2006 Jul 11;16(13):1295-302. Epub 2006 May 25. PMID:16730176 doi:10.1016/j.cub.2006.05.022
- ↑ Lenain C, Bauwens S, Amiard S, Brunori M, Giraud-Panis MJ, Gilson E. The Apollo 5' exonuclease functions together with TRF2 to protect telomeres from DNA repair. Curr Biol. 2006 Jul 11;16(13):1303-10. Epub 2006 May 25. PMID:16730175 doi:10.1016/j.cub.2006.05.021
- ↑ Demuth I, Bradshaw PS, Lindner A, Anders M, Heinrich S, Kallenbach J, Schmelz K, Digweed M, Meyn MS, Concannon P. Endogenous hSNM1B/Apollo interacts with TRF2 and stimulates ATM in response to ionizing radiation. DNA Repair (Amst). 2008 Aug 2;7(8):1192-201. doi: 10.1016/j.dnarep.2008.03.020., Epub 2008 May 12. PMID:18468965 doi:10.1016/j.dnarep.2008.03.020
- ↑ Bae JB, Mukhopadhyay SS, Liu L, Zhang N, Tan J, Akhter S, Liu X, Shen X, Li L, Legerski RJ. Snm1B/Apollo mediates replication fork collapse and S Phase checkpoint activation in response to DNA interstrand cross-links. Oncogene. 2008 Aug 28;27(37):5045-56. doi: 10.1038/onc.2008.139. Epub 2008 May, 12. PMID:18469862 doi:10.1038/onc.2008.139
- ↑ Liu L, Akhter S, Bae JB, Mukhopadhyay SS, Richie CT, Liu X, Legerski R. SNM1B/Apollo interacts with astrin and is required for the prophase cell cycle checkpoint. Cell Cycle. 2009 Feb 15;8(4):628-38. Epub 2009 Feb 7. PMID:19197158
- ↑ Anders M, Mattow J, Digweed M, Demuth I. Evidence for hSNM1B/Apollo functioning in the HSP70 mediated DNA damage response. Cell Cycle. 2009 Jun 1;8(11):1725-32. Epub 2009 Jun 1. PMID:19411856
- ↑ Ye J, Lenain C, Bauwens S, Rizzo A, Saint-Leger A, Poulet A, Benarroch D, Magdinier F, Morere J, Amiard S, Verhoeyen E, Britton S, Calsou P, Salles B, Bizard A, Nadal M, Salvati E, Sabatier L, Wu Y, Biroccio A, Londono-Vallejo A, Giraud-Panis MJ, Gilson E. TRF2 and apollo cooperate with topoisomerase 2alpha to protect human telomeres from replicative damage. Cell. 2010 Jul 23;142(2):230-42. doi: 10.1016/j.cell.2010.05.032. PMID:20655466 doi:10.1016/j.cell.2010.05.032
- ↑ Allerston CK, Lee SY, Newman JA, Schofield CJ, McHugh PJ, Gileadi O. The structures of the SNM1A and SNM1B/Apollo nuclease domains reveal a potential basis for their distinct DNA processing activities. Nucleic Acids Res. 2015 Dec 15;43(22):11047-60. doi: 10.1093/nar/gkv1256. Epub, 2015 Nov 17. PMID:26582912 doi:http://dx.doi.org/10.1093/nar/gkv1256
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