FATC Domain Deletion Compromises ATM Protein Stability, Blocks Lymphocyte Development, and Promotes Lymphomagenesis

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2021 Feb 4

PMID 33536256

Citations 4

Authors

Maja Milanovic

Zhengping Shao

Verna M Estes

Xiaobin S Wang

Demis Menolfi

Xiaohui Lin

Brian J Lee

Jun Xu

Olivia M Cupo

Dong Wang

Shan Zha

Affiliations

Soon will be listed here.

Abstract

Ataxia-telangiectasia mutated (ATM) kinase is a master regulator of the DNA damage response, and loss of ATM leads to primary immunodeficiency and greatly increased risk for lymphoid malignancies. The FATC domain is conserved in phosphatidylinositol-3-kinase-related protein kinases (PIKKs). Truncation mutation in the FATC domain (R3047X) selectively compromised reactive oxygen species-induced ATM activation in cell-free assays. In this article, we show that in mouse models, knock-in ATM-R3057X mutation (⁠ ⁠, corresponding to R3047X in human ATM) severely compromises ATM protein stability and causes T cell developmental defects, B cell Ig class-switch recombination defects, and infertility resembling ATM-null. The residual ATM-R3057X protein retains minimal yet functional measurable DNA damage-induced checkpoint activation and significantly delays lymphomagenesis in ⁠ ⁠ mice compared with ⁠ ⁠. Together, these results support a physiological role of the FATC domain in ATM protein stability and show that the presence of minimal residual ATM-R3057X protein can prevent growth retardation and delay tumorigenesis without restoring lymphocyte development and fertility.

Citing Articles

Ageing microenvironment mediates lymphocyte carcinogenesis and lymphoma drug resistance: From mechanisms to clinical therapy (Review).

Zhang Y, Chu J, Hou Q, Qian S, Wang Z, Yang Q Int J Oncol. 2024; 64(6).

PMID: 38757347 PMC: 11095602. DOI: 10.3892/ijo.2024.5653.

[High expression of CCBE1 in adjacent tissues of tongue squamous cell carcinoma is correlated with pericancerous lymphatic vessel proliferation and poor 5-year survival outcomes].

Zhong J, Wang J, Ye X, Fan S, Wang Y, Chen W Nan Fang Yi Ke Da Xue Xue Bao. 2022; 42(10):1545-1551.

PMID: 36329590 PMC: 9637508. DOI: 10.12122/j.issn.1673-4254.2022.10.15.

ATM Kinase Dead: From Ataxia Telangiectasia Syndrome to Cancer.

Putti S, Giovinazzo A, Merolle M, Falchetti M, Pellegrini M Cancers (Basel). 2021; 13(21).

PMID: 34771661 PMC: 8583659. DOI: 10.3390/cancers13215498.

DNA damage-induced phosphorylation of CtIP at a conserved ATM/ATR site T855 promotes lymphomagenesis in mice.

Wang X, Menolfi D, Wu-Baer F, Fangazio M, Meyer S, Shao Z Proc Natl Acad Sci U S A. 2021; 118(38).

PMID: 34521752 PMC: 8463888. DOI: 10.1073/pnas.2105440118.

References

Paiano J, Wu W, Yamada S, Sciascia N, Callen E, Paola Cotrim A . ATM and PRDM9 regulate SPO11-bound recombination intermediates during meiosis. Nat Commun. 2020; 11(1):857. PMC: 7016097. DOI: 10.1038/s41467-020-14654-w. View

Liyanage M, Weaver Z, Barlow C, Coleman A, Pankratz D, Anderson S . Abnormal rearrangement within the alpha/delta T-cell receptor locus in lymphomas from Atm-deficient mice. Blood. 2000; 96(5):1940-6. View

Westphal C, Rowan S, Schmaltz C, Elson A, Fisher D, Leder P . atm and p53 cooperate in apoptosis and suppression of tumorigenesis, but not in resistance to acute radiation toxicity. Nat Genet. 1997; 16(4):397-401. DOI: 10.1038/ng0897-397. View

Bredemeyer A, Sharma G, Huang C, Helmink B, Walker L, Khor K . ATM stabilizes DNA double-strand-break complexes during V(D)J recombination. Nature. 2006; 442(7101):466-70. DOI: 10.1038/nature04866. View

Lange J, Yamada S, Tischfield S, Pan J, Kim S, Zhu X . The Landscape of Mouse Meiotic Double-Strand Break Formation, Processing, and Repair. Cell. 2016; 167(3):695-708.e16. PMC: 5117687. DOI: 10.1016/j.cell.2016.09.035. View

Morrell D, Cromartie E, Swift M . Mortality and cancer incidence in 263 patients with ataxia-telangiectasia. J Natl Cancer Inst. 1986; 77(1):89-92. View

Pellegrini M, Celeste A, Difilippantonio S, Guo R, Wang W, Feigenbaum L . Autophosphorylation at serine 1987 is dispensable for murine Atm activation in vivo. Nature. 2006; 443(7108):222-5. DOI: 10.1038/nature05112. View

Spring K, Cross S, Li C, Watters D, Waring P, Ahangari F . Atm knock-in mice harboring an in-frame deletion corresponding to the human ATM 7636del9 common mutation exhibit a variant phenotype. Cancer Res. 2001; 61(11):4561-8. View

Li G, Alt F, Cheng H, Brush J, Goff P, Murphy M . Lymphocyte-specific compensation for XLF/cernunnos end-joining functions in V(D)J recombination. Mol Cell. 2008; 31(5):631-40. PMC: 2630261. DOI: 10.1016/j.molcel.2008.07.017. View

10.

Lumsden J, McCarty T, Petiniot L, Shen R, Barlow C, Wynn T . Immunoglobulin class switch recombination is impaired in Atm-deficient mice. J Exp Med. 2004; 200(9):1111-21. PMC: 2211853. DOI: 10.1084/jem.20041074. View

11.

McKinnon P . Genome integrity and disease prevention in the nervous system. Genes Dev. 2017; 31(12):1180-1194. PMC: 5558921. DOI: 10.1101/gad.301325.117. View

12.

Yang H, Rudge D, Koos J, Vaidialingam B, Yang H, Pavletich N . mTOR kinase structure, mechanism and regulation. Nature. 2013; 497(7448):217-23. PMC: 4512754. DOI: 10.1038/nature12122. View

13.

Kitagawa R, Kastan M . The ATM-dependent DNA damage signaling pathway. Cold Spring Harb Symp Quant Biol. 2006; 70:99-109. DOI: 10.1101/sqb.2005.70.002. View

14.

Yamamoto K, Wang Y, Jiang W, Liu X, Dubois R, Lin C . Kinase-dead ATM protein causes genomic instability and early embryonic lethality in mice. J Cell Biol. 2012; 198(3):305-13. PMC: 3413350. DOI: 10.1083/jcb.201204098. View

15.

Dong J, Panchakshari R, Zhang T, Zhang Y, Hu J, Volpi S . Orientation-specific joining of AID-initiated DNA breaks promotes antibody class switching. Nature. 2015; 525(7567):134-139. PMC: 4592165. DOI: 10.1038/nature14970. View

16.

Borghesani P, Alt F, Bottaro A, Davidson L, Aksoy S, Rathbun G . Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice. Proc Natl Acad Sci U S A. 2000; 97(7):3336-41. PMC: 16240. DOI: 10.1073/pnas.97.7.3336. View

17.

Wang X, Lee B, Zha S . The recent advances in non-homologous end-joining through the lens of lymphocyte development. DNA Repair (Amst). 2020; 94:102874. PMC: 7885906. DOI: 10.1016/j.dnarep.2020.102874. View

18.

Sun Y, Jiang X, Chen S, Fernandes N, Price B . A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM. Proc Natl Acad Sci U S A. 2005; 102(37):13182-7. PMC: 1197271. DOI: 10.1073/pnas.0504211102. View

19.

Liu X, Wang X, Lee B, Wu-Baer F, Lin X, Shao Z . CtIP is essential for early B cell proliferation and development in mice. J Exp Med. 2019; 216(7):1648-1663. PMC: 6605744. DOI: 10.1084/jem.20181139. View

20.

Liu X, Jiang W, Dubois R, Yamamoto K, Wolner Z, Zha S . Overlapping functions between XLF repair protein and 53BP1 DNA damage response factor in end joining and lymphocyte development. Proc Natl Acad Sci U S A. 2012; 109(10):3903-8. PMC: 3309750. DOI: 10.1073/pnas.1120160109. View