Phosphorylated BLM peptide acts as an agonist for DNA damage response.

Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE

Publication: 1992- : Oxford : Oxford University Press
Original Publication: London, Information Retrieval ltd.

DNA Damage* ; RecQ Helicases*/metabolism ; RecQ Helicases*/genetics ; RecQ Helicases*/chemistry; Animals ; Ataxia Telangiectasia Mutated Proteins/metabolism ; Phosphorylation ; Humans ; Mice ; Cell Cycle Proteins/metabolism ; DNA-Binding Proteins/metabolism ; Nuclear Proteins/metabolism ; Tumor Suppressor Protein p53/metabolism ; Female ; Mice, Knockout ; Cell Line ; Peptides/chemistry ; Peptides/metabolism ; DNA Repair ; Tumor Suppressor Proteins/metabolism ; Protein Serine-Threonine Kinases/metabolism

Upon exposure to ionizing irradiation, the MRE11-RAD50-NBS1 complex potentiates the recruitment of ATM (ataxia-telangiectasia mutated) kinase to the double-strand breaks. We show that the lack of BLM causes a decrease in the autophosphorylation of ATM in mice mammary glands, which have lost one or both copies of BLM. In isogenic human cells, the DNA damage response (DDR) pathway was dampened in the absence of BLM, which negatively affected the recruitment of DDR factors onto the chromatin, thereby indicating a direct role of BLM in augmenting DDR. Mechanistically, this was due to the BLM-dependent dissociation of inactive ATM dimers into active monomers. Fragmentation analysis of BLM followed by kinase assays revealed a 20-mer BLM peptide (91-110 aa), sufficient to enhance ATM-dependent p53 phosphorylation. ATM-mediated phosphorylation of BLM at Thr99 within BLM (91-110) peptide enhanced ATM kinase activity due to its interaction with NBS1 and causing ATM monomerization. Delivery of phosphomimetic T99E counterpart of BLM (91-110 aa) peptide led to ATM activation followed by restoration of the DDR even in the absence of ionizing irradiation (both in cells and in BLM knockout mice), indicating its role as a DDR agonist, which can be potentially used to prevent the initiation of neoplastic transformation.
(© The Author(s) 2025. Published by Oxford University Press on behalf of Nucleic Acids Research.)

DNA Repair (Amst). 2021 Dec;108:103232. (PMID: 34678589)
Sci Rep. 2017 Sep 11;7(1):11144. (PMID: 28894253)
Nature. 2005 Apr 14;434(7035):864-70. (PMID: 15829956)
Nat Commun. 2015 Jul 29;6:7677. (PMID: 26220524)
EMBO J. 2003 Oct 15;22(20):5612-21. (PMID: 14532133)
J Cell Biol. 2008 Apr 21;181(2):213-26. (PMID: 18411307)
Mutat Res. 2020 May - Dec;821:111695. (PMID: 32304909)
Mol Cell. 2012 May 11;46(3):351-61. (PMID: 22464731)
Cold Spring Harb Perspect Biol. 2013 Sep 01;5(9):. (PMID: 24003211)
EMBO J. 2010 May 19;29(10):1713-25. (PMID: 20389284)
Nature. 2005 Apr 14;434(7035):907-13. (PMID: 15829965)
J Biol Chem. 2013 May 3;288(18):12840-51. (PMID: 23525106)
Breast Cancer Res. 2015 May 03;17:65. (PMID: 25935535)
J Cell Biol. 2004 Sep 13;166(6):801-13. (PMID: 15364958)
Genes Dev. 2007 Dec 1;21(23):3085-94. (PMID: 18003860)
Nat Struct Mol Biol. 2021 Oct;28(10):789-798. (PMID: 34556870)
Front Genet. 2021 Mar 12;12:634789. (PMID: 33777104)
J Cell Sci. 2009 Sep 1;122(Pt 17):3093-103. (PMID: 19671661)
Cell Rep. 2018 Aug 7;24(6):1471-1483. (PMID: 30089259)
J Cell Biol. 2007 Jul 2;178(1):9-14. (PMID: 17591918)
Nat Rev Mol Cell Biol. 2021 Dec;22(12):796-814. (PMID: 34429537)
Carcinogenesis. 2008 Jan;29(1):52-61. (PMID: 17984114)
Genes Dev. 2011 Feb 15;25(4):350-62. (PMID: 21325134)
Cancer Res. 2004 Dec 15;64(24):9152-9. (PMID: 15604286)
EMBO Rep. 2008 Aug;9(8):795-801. (PMID: 18583988)
Genome Integr. 2010 Nov 04;1(1):14. (PMID: 21050475)
ACS Cent Sci. 2019 Oct 23;5(10):1648-1662. (PMID: 31660434)
Nature. 2003 Jan 30;421(6922):499-506. (PMID: 12556884)
Cancer Res. 2023 Dec 1;83(23):3861-3867. (PMID: 37668528)
Blood. 2000 Sep 1;96(5):1940-6. (PMID: 10961898)
Cell Death Discov. 2024 Jun 25;10(1):302. (PMID: 38914566)
Elife. 2022 Jan 25;11:. (PMID: 35076389)
Hum Mol Genet. 2001 Mar 1;10(5):519-28. (PMID: 11181576)
Annu Rev Biochem. 2015;84:711-38. (PMID: 25580527)
Mol Cell. 2017 Jan 5;65(1):91-104. (PMID: 27939942)
Nucleic Acids Res. 2013 Jan;41(Database issue):D991-5. (PMID: 23193258)
Proc Natl Acad Sci U S A. 2018 Oct 2;115(40):10016-10021. (PMID: 30224471)
Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1446-51. (PMID: 16432227)
Biochem Soc Trans. 2009 Jun;37(Pt 3):553-9. (PMID: 19442250)
J Biol Chem. 2002 Aug 23;277(34):30515-23. (PMID: 12034743)
Science. 2005 Apr 22;308(5721):551-4. (PMID: 15790808)
J Cell Biol. 2008 Apr 21;181(2):227-40. (PMID: 18411308)
Cell Rep. 2013 Oct 17;5(1):21-8. (PMID: 24095737)
J Cell Biol. 2020 Jun 1;219(6):. (PMID: 32346721)
Cell Rep. 2018 Jul 24;24(4):947-961.e7. (PMID: 30044990)
Mol Cell. 2006 Jan 20;21(2):187-200. (PMID: 16427009)
Nat Struct Mol Biol. 2015 Sep;22(9):736-43. (PMID: 26280532)
EMBO J. 2019 Sep 16;38(18):e101801. (PMID: 31393028)
Genes Dev. 2000 Apr 15;14(8):927-39. (PMID: 10783165)
Mol Cell. 2010 Oct 22;40(2):179-204. (PMID: 20965415)
Mol Cancer Res. 2010 Sep;8(9):1234-47. (PMID: 20719863)
J Cell Sci. 2013 Aug 15;126(Pt 16):3782-95. (PMID: 23750012)
EMBO J. 2013 Jun 12;32(12):1778-92. (PMID: 23708797)
Mol Cell Biol. 2004 Feb;24(3):1279-91. (PMID: 14729972)
Nucleic Acids Res. 2018 Jan 4;46(D1):D661-D667. (PMID: 29136241)
Science. 2008 Jun 13;320(5882):1507-10. (PMID: 18483401)
Nucleic Acids Res. 2022 Jan 7;50(D1):D543-D552. (PMID: 34723319)
Nat Commun. 2019 Apr 5;10(1):1577. (PMID: 30952868)
Nat Commun. 2018 Mar 9;9(1):1016. (PMID: 29523790)
Invest New Drugs. 2022 Jun;40(3):596-605. (PMID: 35150356)
J Clin Invest. 2024 Feb 29;134(8):. (PMID: 38421735)

National Institute of Immunology; National Institute of Biomedical Genomics; BT/PR41739/BRB/10/1974/2021 Department of Biotechnology, Ministry of Science and Technology, India; 58/14/17/2021-BRNS Board of Research in Nuclear Sciences; Anusandhan National Research Foundation (ANRF); CRG/2020/000125 Science and Engineering Research Board; 27/0387/23/EMR-II Council of Scientific and Industrial Research, India; IFC/6803-1/2022 Indo-French Centre for the Promotion of Advanced Research; JBR/2023/000020 Anusandhan National Research Foundation (ANRF), India

EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins)
EC 3.6.1.- (Bloom syndrome protein)
EC 3.6.4.12 (RecQ Helicases)
0 (Cell Cycle Proteins)
0 (DNA-Binding Proteins)
0 (Nuclear Proteins)
0 (Tumor Suppressor Protein p53)
EC 2.7.11.1 (ATM protein, human)
EC 2.7.11.1 (Atm protein, mouse)
0 (NBN protein, human)
0 (Peptides)
0 (Tumor Suppressor Proteins)
EC 2.7.11.1 (Protein Serine-Threonine Kinases)

Date Created: 20250225 Date Completed: 20250509 Latest Revision: 20250509

20250510

PMC11851105

10.1093/nar/gkaf106

39997217