DNA Damage in Stem Cells Activates P21, Inhibits P53, and Induces Symmetric Self-renewing Divisions

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2013 Feb 19

PMID 23417300

Citations 72

Authors

Alessandra Insinga

Angelo Cicalese

Mario Faretta

Barbara Gallo

Luisa Albano

Simona Ronzoni

Laura Furia

Andrea Viale

Pier Giuseppe Pelicci

Affiliations

Soon will be listed here.

Abstract

DNA damage leads to a halt in proliferation owing to apoptosis or senescence, which prevents transmission of DNA alterations. This cellular response depends on the tumor suppressor p53 and functions as a powerful barrier to tumor development. Adult stem cells are resistant to DNA damage-induced apoptosis or senescence, however, and how they execute this response and suppress tumorigenesis is unknown. We show that irradiation of hematopoietic and mammary stem cells up-regulates the cell cycle inhibitor p21, a known target of p53, which prevents p53 activation and inhibits p53 basal activity, impeding apoptosis and leading to cell cycle entry and symmetric self-renewing divisions. p21 also activates DNA repair, limiting DNA damage accumulation and self-renewal exhaustion. Stem cells with moderate DNA damage and diminished self-renewal persist after irradiation, however. These findings suggest that stem cells have evolved a unique, p21-dependent response to DNA damage that leads to their immediate expansion and limits their long-term survival.

Citing Articles

Chronic kidney disease and aging: dissecting the p53/p21 pathway as a therapeutic target.

Goyal K, Afzal M, Altamimi A, Babu M, Ballal S, Kaur I Biogerontology. 2024; 26(1):32.

PMID: 39725742 DOI: 10.1007/s10522-024-10173-z.

Personalized oncology in pheochromocytomas and paragangliomas: integrating genetic analysis with machine learning.

Abida , Alzahrani A, Alhuthali H, Alkathiri A, Almaghrabi R, Alshehri J Med Oncol. 2024; 41(11):290.

PMID: 39420072 DOI: 10.1007/s12032-024-02532-0.

CYP2E1 in 1,4-dioxane metabolism and liver toxicity: insights from CYP2E1 knockout mice study.

Wang Y, Charkoftaki G, Orlicky D, Davidson E, Aalizadeh R, Sun N Arch Toxicol. 2024; 98(10):3241-3257.

PMID: 39192018 PMC: 11500436. DOI: 10.1007/s00204-024-03811-5.

A single dose of radiation elicits comparable acute salivary gland injury to fractionated radiation.

Johnson A, Elder S, McKendrick J, Hegarty L, Mercer E, Emmerson E Dis Model Mech. 2024; 17(8).

PMID: 39086326 PMC: 11361643. DOI: 10.1242/dmm.050733.

G2 arrest primes hematopoietic stem cells for megakaryopoiesis.

Garyn C, Bover O, Murray J, Ma J, Salas-Briceno K, Ross S Cell Rep. 2024; 43(7):114388.

PMID: 38935497 PMC: 11330628. DOI: 10.1016/j.celrep.2024.114388.

References

Cazzalini O, Scovassi A, Savio M, Stivala L, Prosperi E . Multiple roles of the cell cycle inhibitor p21(CDKN1A) in the DNA damage response. Mutat Res. 2010; 704(1-3):12-20. DOI: 10.1016/j.mrrev.2010.01.009. View

Qiu W, Carson-Walter E, Liu H, Epperly M, Greenberger J, Zambetti G . PUMA regulates intestinal progenitor cell radiosensitivity and gastrointestinal syndrome. Cell Stem Cell. 2008; 2(6):576-83. PMC: 2892934. DOI: 10.1016/j.stem.2008.03.009. View

Meek D . Tumour suppression by p53: a role for the DNA damage response?. Nat Rev Cancer. 2009; 9(10):714-23. DOI: 10.1038/nrc2716. View

Rossi D, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman I . Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature. 2007; 447(7145):725-9. DOI: 10.1038/nature05862. View

Orkin S, Zon L . Hematopoiesis: an evolving paradigm for stem cell biology. Cell. 2008; 132(4):631-44. PMC: 2628169. DOI: 10.1016/j.cell.2008.01.025. View

Sedelnikova O, Horikawa I, Redon C, Nakamura A, Zimonjic D, Popescu N . Delayed kinetics of DNA double-strand break processing in normal and pathological aging. Aging Cell. 2007; 7(1):89-100. DOI: 10.1111/j.1474-9726.2007.00354.x. View

Cicalese A, Bonizzi G, Pasi C, Faretta M, Ronzoni S, Giulini B . The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells. Cell. 2009; 138(6):1083-95. DOI: 10.1016/j.cell.2009.06.048. View

Milyavsky M, Gan O, Trottier M, Komosa M, Tabach O, Notta F . A distinctive DNA damage response in human hematopoietic stem cells reveals an apoptosis-independent role for p53 in self-renewal. Cell Stem Cell. 2010; 7(2):186-97. DOI: 10.1016/j.stem.2010.05.016. View

Hendry J, Cai W, Roberts S, Potten C . p53 deficiency sensitizes clonogenic cells to irradiation in the large but not the small intestine. Radiat Res. 1997; 148(3):254-9. View

10.

Levine A, Oren M . The first 30 years of p53: growing ever more complex. Nat Rev Cancer. 2009; 9(10):749-58. PMC: 2771725. DOI: 10.1038/nrc2723. View

11.

van Os R, Kamminga L, Ausema A, Bystrykh L, Draijer D, van Pelt K . A Limited role for p21Cip1/Waf1 in maintaining normal hematopoietic stem cell functioning. Stem Cells. 2006; 25(4):836-43. DOI: 10.1634/stemcells.2006-0631. View

12.

Seita J, Rossi D, Weissman I . Differential DNA damage response in stem and progenitor cells. Cell Stem Cell. 2010; 7(2):145-7. DOI: 10.1016/j.stem.2010.07.006. View

13.

Ishikawa K, Ishii H, Saito T . DNA damage-dependent cell cycle checkpoints and genomic stability. DNA Cell Biol. 2006; 25(7):406-11. DOI: 10.1089/dna.2006.25.406. View

14.

Weissman I, Shizuru J . The origins of the identification and isolation of hematopoietic stem cells, and their capability to induce donor-specific transplantation tolerance and treat autoimmune diseases. Blood. 2008; 112(9):3543-53. PMC: 2574516. DOI: 10.1182/blood-2008-08-078220. View

15.

Sotiropoulou P, Candi A, Mascre G, De Clercq S, Youssef K, Lapouge G . Bcl-2 and accelerated DNA repair mediates resistance of hair follicle bulge stem cells to DNA-damage-induced cell death. Nat Cell Biol. 2010; 12(6):572-82. DOI: 10.1038/ncb2059. View

16.

Merritt A, Potten C, Kemp C, Hickman J, Balmain A, Lane D . The role of p53 in spontaneous and radiation-induced apoptosis in the gastrointestinal tract of normal and p53-deficient mice. Cancer Res. 1994; 54(3):614-7. View

17.

Blanpain C, Mohrin M, Sotiropoulou P, Passegue E . DNA-damage response in tissue-specific and cancer stem cells. Cell Stem Cell. 2011; 8(1):16-29. DOI: 10.1016/j.stem.2010.12.012. View

18.

Nijnik A, Woodbine L, Marchetti C, Dawson S, Lambe T, Liu C . DNA repair is limiting for haematopoietic stem cells during ageing. Nature. 2007; 447(7145):686-90. DOI: 10.1038/nature05875. View

19.

Xu H, Balakrishnan K, Malaterre J, Beasley M, Yan Y, Essers J . Rad21-cohesin haploinsufficiency impedes DNA repair and enhances gastrointestinal radiosensitivity in mice. PLoS One. 2010; 5(8):e12112. PMC: 2920816. DOI: 10.1371/journal.pone.0012112. View

20.

Aliouat-Denis C, Dendouga N, Van den Wyngaert I, Goehlmann H, Steller U, van de Weyer I . p53-independent regulation of p21Waf1/Cip1 expression and senescence by Chk2. Mol Cancer Res. 2005; 3(11):627-34. DOI: 10.1158/1541-7786.MCR-05-0121. View