Reader TTS

ABSTRACT The hereditary autosomal recessive disease ataxia telangiectasia (A-T) is caused by mutation in the DNA damage kinase ATM. ATM’s main function is to orchestrate DNA repair, thereby

maintaining genomic stability. ATM activity is increased in response to several stimuli, including ionising radiation (IR) and hypotonic stress. DNMT1-associated protein 1 (DMAP1) is a

member of the TIP60-p400 histone acetyl transferase (HAT) complex, which acetylates histone H4 at lysine 16 (H4K16) to affect chromatin relaxation and modulate ATM activation. Here we

demonstrate that DMAP1 is required for both modes of ATM activation. Knockdown of DMAP1 impaired IR-induced ATM activation and consequently resulted in radiosensitivity and impaired the G2/M

checkpoint. Moreover, DMAP1 was also required for efficient ATM signalling in response to hypotonic stress. Overexpression of DMAP1 increased IR-induced ATM substrate phosphorylation,

suggesting that DMAP1 function is rate limiting for ATM signalling. DMAP1 associated with TIP60-dependent HAT activity, and depletion of DMAP1 reduced H4K16 acetylation in response to DNA

damage. Treatment with histone deacetylase inhibitors rescued IR-induced ATM signalling in _Dmap1_-depleted cells. These results suggest that DMAP1 is a critical regulator of ATM activity

and function. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe

to this journal Receive 50 print issues and online access $259.00 per year only $5.18 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF

Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact

customer support SIMILAR CONTENT BEING VIEWED BY OTHERS DAXX-ATRX REGULATION OF P53 CHROMATIN BINDING AND DNA DAMAGE RESPONSE Article Open access 26 August 2022 TRIM24 IS CRITICAL FOR THE

CELLULAR RESPONSE TO DNA DOUBLE-STRAND BREAKS THROUGH REGULATING THE RECRUITMENT OF MRN COMPLEX Article 22 December 2022 PARP INHIBITION-ASSOCIATED HETEROCHROMATIN CONFERS INCREASED DNA

REPLICATION STRESS AND VULNERABILITY TO ATR INHIBITION IN SMARCA4-DEFICIENT CELLS Article Open access 28 January 2025 REFERENCES * Chun HH, Gatti RA . Ataxia-telangiectasia, an evolving

phenotype. _DNA Repair (Amst)_ 2004; 3 (8-9): 1187–1196. Article  CAS  Google Scholar  * Frappart PO, McKinnon PJ . Ataxia-telangiectasia and related diseases. _Neuromolecular Med_ 2006; 8

(4): 495–511. Article  CAS  Google Scholar  * Kuhne M, Riballo E, Rief N, Rothkamm K, Jeggo PA, Lobrich M . A double-strand break repair defect in ATM-deficient cells contributes to

radiosensitivity. _Cancer Res_ 2004; 64 (2): 500–508. Article  Google Scholar  * Shiloh Y, Tabor E, Becker Y . Colony-forming ability of ataxia-telangiectasia skin fibroblasts is an

indicator of their early senescence and increased demand for growth factors. _Exp Cell Res_ 1982; 140 (1): 191–199. Article  CAS  Google Scholar  * Bakkenist CJ, Kastan MB . Initiating

cellular stress responses. _Cell_ 2004; 118 (1): 9–17. Article  CAS  Google Scholar  * Durocher D, Jackson SP . DNA-PK ATM and ATR as sensors of DNA damage: variations on a theme? _Curr Opin

Cell Biol_ 2001; 13 (2): 225–231. Article  CAS  Google Scholar  * Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER, Hurov KE, Luo J _et al_. ATM and ATR substrate analysis reveals

extensive protein networks responsive to DNA damage. _Science_ 2007; 316 (5828): 1160–1166. Article  CAS  Google Scholar  * Lukas J, Lukas C, Bartek J . Mammalian cell cycle checkpoints:

signalling pathways and their organization in space and time. _DNA Repair (Amst)_ 2004; 3 (8-9): 997–1007. Article  CAS  Google Scholar  * Bakkenist CJ, Kastan MB . DNA damage activates ATM

through intermolecular autophosphorylation and dimer dissociation. _Nature_ 2003; 421 (6922): 499–506. Article  CAS  Google Scholar  * Shiloh Y . ATM and related protein kinases:

safeguarding genome integrity. _Nat Rev Cancer_ 2003; 3 (3): 155–168. Article  CAS  Google Scholar  * Kim ST, Lim DS, Canman CE, Kastan MB . Substrate specificities and identification of

putative substrates of ATM kinase family members. _J Biol Chem_ 1999; 274 (53): 37538–37543. Article  CAS  Google Scholar  * Uziel T, Lerenthal Y, Moyal L, Andegeko Y, Mittelman L, Shiloh Y

. Requirement of the MRN complex for ATM activation by DNA damage. _EMBO J_ 2003; 22 (20): 5612–5621. Article  CAS  Google Scholar  * Lee JH, Paull TT . Activation and regulation of ATM

kinase activity in response to DNA double-strand breaks. _Oncogene_ 2007; 26 (56): 7741–7748. Article  CAS  Google Scholar  * Wu J, Chen Y, Lu LY, Wu Y, Paulsen MT, Ljungman M _et al_. Chfr

and RNF8 synergistically regulate ATM activation. _Nat Struct Mol Biol_ 2011; 18 (7): 761–768. Article  CAS  Google Scholar  * Murr R, Loizou JI, Yang YG, Cuenin C, Li H, Wang ZQ _et al_.

Histone acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of DNA double-strand breaks. _Nat Cell Biol_ 2006; 8 (1): 91–99. Article  CAS  Google Scholar  * Rountree

MR, Bachman KE, Baylin SB . DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. _Nat Genet_ 2000; 25 (3): 269–277. Article  CAS  Google Scholar  * Cai Y,

Jin J, Tomomori-Sato C, Sato S, Sorokina I, Parmely TJ _et al_. Identification of new subunits of the multiprotein mammalian TRRAP/TIP60-containing histone acetyltransferase complex. _J Biol

Chem_ 2003; 278 (44): 42733–42736. Article  CAS  Google Scholar  * Doyon Y, Selleck W, Lane WS, Tan S, Cote J . Structural and functional conservation of the NuA4 histone acetyltransferase

complex from yeast to humans. _Mol Cell Biol_ 2004; 24 (5): 1884–1896. Article  CAS  Google Scholar  * Boyer LA, Langer MR, Crowley KA, Tan S, Denu JM, Peterson CL . Essential role for the

SANT domain in the functioning of multiple chromatin remodeling enzymes. _Mol Cell_ 2002; 10 (4): 935–942. Article  CAS  Google Scholar  * Boyer LA, Latek RR, Peterson CL . The SANT domain:

a unique histone-tail-binding module? _Nat Rev Mol Cell Biol_ 2004; 5 (2): 158–163. Article  CAS  Google Scholar  * Negishi M, Chiba T, Saraya A, Miyagi S, Iwama A . Dmap1 plays an essential

role in the maintenance of genome integrity through the DNA repair process. _Genes Cells_ 2009; 14 (11): 1347–1357. Article  CAS  Google Scholar  * Lavin M . Ataxia-telangiectasia: from a

rare disorder to a paradigm for cell signalling and cancer. _Nat Rev Mol Cell Biol_ 2008; 9 (10): 759–769. Article  CAS  Google Scholar  * Kusch T, Florens L, Macdonald WH, Swanson SK,

Glaser RL, Yates JR _et al_. Acetylation by Tip60 is required for selective histone variant exchange at DNA lesions. _Science_ 2004; 306 (5704): 2084–2087. Article  CAS  Google Scholar  *

Sharma GG, So S, Gupta A, Kumar R, Cayrou C, Avvakumov N _et al_. MOF and histone H4 acetylation at lysine 16 are critical for DNA damage response and double-strand break repair. _Mol Cell

Biol_ 2010; 30 (14): 3582–3595. Article  CAS  Google Scholar  * Kim YC, Gerlitz G, Furusawa T, Catez F, Nussenzweig A, Oh KS _et al_. Activation of ATM depends on chromatin interactions

occurring before induction of DNA damage. _Nat Cell Biol_ 2009; 11 (1): 92–96. Article  CAS  Google Scholar  * Sun Y, Jiang X, Chen S, Fernandes N, Price BD . A role for the Tip60 histone

acetyltransferase in the acetylation and activation of ATM. _Proc Natl Acad Sci USA_ 2005; 102 (37): 13182–13187. Article  CAS  Google Scholar  * Sun Y, Xu Y, Roy K, Price BD . DNA

damage-induced acetylation of lysine 3016 of ATM activates ATM kinase activity. _Mol Cell Biol_ 2007; 27 (24): 8502–8509. Article  CAS  Google Scholar  * Fraga MF, Ballestar E, Villar-Garea

A, Boix-Chornet M, Espada J, Schotta G _et al_. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. _Nat Genet_ 2005; 37 (4):

391–400. Article  CAS  Google Scholar  * Gorrini C, Squatrito M, Luise C, Syed N, Perna D, Wark L _et al_. Tip60 is a haplo-insufficient tumour suppressor required for an oncogene-induced

DNA damage response. _Nature_ 2007; 448 (7157): 1063–1067. Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS Support was given from the Experimental HistoPathology Unit,

Bioinformatics and Biostatistics, the Equipment Park, Biological Resources and the FACS Lab in the London Research Institute (CR-UK). We thank Dr Cremona and Dr Kanu for critical reading of

the manuscript and the Mammalian Genetics Lab for input and discussions. This work was supported by an ERC grant (281661 ATMINDDR) to AB. The London Research Institute is funded by Cancer

Research UK. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Mammalian Genetics Lab, Cancer Research UK, London Research Institute, London, UK K Penicud & A Behrens Authors * K Penicud

View author publications You can also search for this author inPubMed Google Scholar * A Behrens View author publications You can also search for this author inPubMed Google Scholar

CORRESPONDING AUTHOR Correspondence to A Behrens. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no conflict of interest. ADDITIONAL INFORMATION Supplementary Information

accompanies the paper on the Oncogene website SUPPLEMENTARY INFORMATION SUPPLEMENTARY FIGURE 1 (JPG 362 KB) SUPPLEMENTARY FIGURE 2 (JPG 598 KB) SUPPLEMENTARY FIGURE 3 (JPG 681 KB)

SUPPLEMENTARY FIGURE 4 (JPG 301 KB) SUPPLEMENTARY FIGURE LEGENDS (DOC 54 KB) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Penicud, K., Behrens, A.

DMAP1 is an essential regulator of ATM activity and function. _Oncogene_ 33, 525–531 (2014). https://doi.org/10.1038/onc.2012.597 Download citation * Received: 19 April 2012 * Revised: 26

October 2012 * Accepted: 26 November 2012 * Published: 14 January 2013 * Issue Date: 23 January 2014 * DOI: https://doi.org/10.1038/onc.2012.597 SHARE THIS ARTICLE Anyone you share the

following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer

Nature SharedIt content-sharing initiative KEYWORDS * DMAP1 * ATM * TIP60 * double-strand break