3sqd

Structural highlights

Function

[PAXI1_HUMAN] Involved in DNA damage response and in transcriptional regulation through histone methyltransferase (HMT) complexes. Plays a role in early development. In DNA damage response is required for cell survival after ionizing radiation. In vitro shown to be involved in the homologous recombination mechanism for the repair of double-strand breaks (DSBs). Its localization to DNA damage foci requires RNF8 and UBE2N. Recruits TP53BP1 to DNA damage foci and, at least in particular repair processes, effective DNA damage response appears to require the association with TP53BP1 phosphorylated by ATM at 'Ser-25'. Together with TP53BP1 regulates ATM association. Recruits PAGR1 to sites of DNA damage and the PAGR1:PAXIP1 complex is required for cell survival in response to DNA damage; the function is probbaly independent of MLL-containing histone methyltransferase (HMT) complexes. Promotes ubiquitination of PCNA following UV irradiation and may regulate recruitment of polymerase eta and RAD51 to chromatin after DNA damage. Proposed to be involved in transcriptional regulation by linking MLL-containing histone methyltransferase (HMT) complexes to gene promoters by interacting with promoter-bound transcription factors such as PAX2. Associates with gene promoters that are known to be regulated by KMT2D/MLL2. During immunoglobulin class switching in activated B-cells is involved in trimethylation of histone H3 at 'Lys-4' and in transcription initiation of downstream switch regions at the immunoglobulin heavy-chain (Igh) locus; this function appears to involve the recruitment of MLL-containing HMT complexes.^{[1] [2] [3] [4] [5] [6]} [H2AX_HUMAN] Variant histone H2A which replaces conventional H2A in a subset of nucleosomes. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling. Required for checkpoint-mediated arrest of cell cycle progression in response to low doses of ionizing radiation and for efficient repair of DNA double strand breaks (DSBs) specifically when modified by C-terminal phosphorylation.^{[7] [8] [9] [10]}

References

1. ↑ Manke IA, Lowery DM, Nguyen A, Yaffe MB. BRCT repeats as phosphopeptide-binding modules involved in protein targeting. Science. 2003 Oct 24;302(5645):636-9. PMID:14576432 doi:http://dx.doi.org/10.1126/science.1088877
2. ↑ Jowsey PA, Doherty AJ, Rouse J. Human PTIP facilitates ATM-mediated activation of p53 and promotes cellular resistance to ionizing radiation. J Biol Chem. 2004 Dec 31;279(53):55562-9. Epub 2004 Sep 27. PMID:15456759 doi:http://dx.doi.org/10.1074/jbc.M411021200
3. ↑ Munoz IM, Jowsey PA, Toth R, Rouse J. Phospho-epitope binding by the BRCT domains of hPTIP controls multiple aspects of the cellular response to DNA damage. Nucleic Acids Res. 2007;35(16):5312-22. Epub 2007 Aug 8. PMID:17690115 doi:http://dx.doi.org/10.1093/nar/gkm493
4. ↑ Patel SR, Kim D, Levitan I, Dressler GR. The BRCT-domain containing protein PTIP links PAX2 to a histone H3, lysine 4 methyltransferase complex. Dev Cell. 2007 Oct;13(4):580-92. PMID:17925232 doi:http://dx.doi.org/10.1016/j.devcel.2007.09.004
5. ↑ Gohler T, Munoz IM, Rouse J, Blow JJ. PTIP/Swift is required for efficient PCNA ubiquitination in response to DNA damage. DNA Repair (Amst). 2008 May 3;7(5):775-87. doi: 10.1016/j.dnarep.2008.02.001., Epub 2008 Mar 18. PMID:18353733 doi:http://dx.doi.org/10.1016/j.dnarep.2008.02.001
6. ↑ Wang X, Takenaka K, Takeda S. PTIP promotes DNA double-strand break repair through homologous recombination. Genes Cells. 2010 Mar;15(3):243-54. doi: 10.1111/j.1365-2443.2009.01379.x. Epub, 2010 Jan 19. PMID:20088963 doi:http://dx.doi.org/10.1111/j.1365-2443.2009.01379.x
7. ↑ Paull TT, Rogakou EP, Yamazaki V, Kirchgessner CU, Gellert M, Bonner WM. A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. Curr Biol. 2000 Jul 27-Aug 10;10(15):886-95. PMID:10959836
8. ↑ Kobayashi J, Tauchi H, Sakamoto S, Nakamura A, Morishima K, Matsuura S, Kobayashi T, Tamai K, Tanimoto K, Komatsu K. NBS1 localizes to gamma-H2AX foci through interaction with the FHA/BRCT domain. Curr Biol. 2002 Oct 29;12(21):1846-51. PMID:12419185
9. ↑ Stewart GS, Wang B, Bignell CR, Taylor AM, Elledge SJ. MDC1 is a mediator of the mammalian DNA damage checkpoint. Nature. 2003 Feb 27;421(6926):961-6. PMID:12607005 doi:10.1038/nature01446
10. ↑ Lukas C, Melander F, Stucki M, Falck J, Bekker-Jensen S, Goldberg M, Lerenthal Y, Jackson SP, Bartek J, Lukas J. Mdc1 couples DNA double-strand break recognition by Nbs1 with its H2AX-dependent chromatin retention. EMBO J. 2004 Jul 7;23(13):2674-83. Epub 2004 Jun 17. PMID:15201865 doi:10.1038/sj.emboj.7600269