title: MUTYH mediates the toxicity of combined DNA 6-thioguanine and UVA radiation.
abstract: The therapeutic thiopurines, including the immunosuppressant azathioprine (Aza) cause the accumulation of the UVA photosensitizer 6-thioguanine (6-TG) in the DNA of the patients' cells. DNA 6-TG and UVA are synergistically cytotoxic and their interaction causes oxidative damage. The MUTYH DNA glycosylase participates in the base excision repair of oxidized DNA bases. Using Mutyh-nullmouse fibroblasts (MEFs) we examined whether MUTYH provides protection against the lethal effects of combined DNA 6-TG/UVA. Surprisingly, Mutyh-null MEFs were more resistant than wild-type MEFs, despite accumulating higher levels of DNA 8-oxo-7,8-dihydroguanine (8-oxoG).Their enhanced 6-TG/UVA resistance reflected the absence of the MUTYH protein and MEFs expressing enzymatically-dead human variants were as sensitive as wild-type cells. Consistent with their enhanced resistance, Mutyh-null cells sustained fewer DNA strand breaks and lower levels of chromosomal damage after 6-TG/UVA. Although 6-TG/UVA treatment caused early checkpoint activation irrespective of the MUTYH status, Mutyh-null cells failed to arrest in S-phase at late time points. MUTYH-dependent toxicity was also apparent in vivo. Mutyh-/- mice survived better than wild-type during a 12-month chronicexposure to Aza/UVA treatments that significantly increased levels of skin DNA 8-oxoG. Two squamous cell skin carcinomas arose in Aza/UVA treated Mutyh-/- mice whereas similarly treated wild-type animals remained tumor-free.
authors: Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Rome, Italy.|Department of Science, University Roma Tre, Rome, Italy.
authors: Francesca
authors: F
authors: Grasso
authors: Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy.
authors: Vitalba
authors: V
authors: Ruggieri
authors: Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Rome, Italy.
authors: Gabriele
authors: G
authors: De Luca
authors: Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Rome, Italy.
authors: Paola
authors: P
authors: Leopardi
authors: Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA) CR-Casaccia, Rome, Italy.
authors: Maria Teresa
authors: MT
authors: Mancuso
authors: Department of Immunohematology and Transfusion Unit, Azienda Ospedaliera Sant'Andrea, Rome, Italy.
authors: Ida
authors: I
authors: Casorelli
authors: Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Rome, Italy.
authors: Pietro
authors: P
authors: Pichierri
authors: Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Herts, UK.
authors: Peter
authors: P
authors: Karran
authors: Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Rome, Italy.
authors: Margherita
authors: M
authors: Bignami
mesh_terms: D000818:Animals; D004247:DNA / Q000378:metabolism*; D045647:DNA Glycosylases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D013866:Thioguanine / Q000009:adverse effects* / Q000378:metabolism; D014162:Transfection; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D004247:DNA; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; D013866:Thioguanine
keywords: 6-thioguanine; MUTYH; UVA; azathioprine
references: DNA Repair (Amst). 2007 Apr 1;6(4):398-409
references: 17129767
references: Aging Cell. 2013 Aug;12(4):695-705
references: 23648059
references: Nucleic Acids Res. 2005 Sep 20;33(16):5094-105
references: 16174844
references: Carcinogenesis. 2008 Apr;29(4):722-8
references: 18258604
references: Oncogene. 2010 Jul 8;29(27):3953-63
references: 20440263
references: Mutat Res. 2013 Mar-Apr;743-744:33-43
references: 23507534
references: J Invest Dermatol. 2005 Jan;124(1):241-7
references: 15654980
references: Proc Natl Acad Sci U S A. 2006 Sep 12;103(37):13765-70
references: 16954188
references: N Engl J Med. 2003 Apr 24;348(17):1681-91
references: 12711744
references: Nat Rev Cancer. 2008 Jan;8(1):24-36
references: 18097462
references: Nucleic Acids Res. 2001 Jul 1;29(13):2802-9
references: 11433026
references: Hum Mol Genet. 2002 Nov 1;11(23):2961-7
references: 12393807
references: J Biol Chem. 2002 Mar 29;277(13):11135-42
references: 11801590
references: Mutat Res. 2005 Oct 15;578(1-2):1-14
references: 16107271
references: Hum Mol Genet. 2014 Jul 15;23(14):3843-52
references: 24569162
references: DNA Repair (Amst). 2010 Jun 4;9(6):604-16
references: 20399712
references: Cancer Res. 2004 Jul 1;64(13):4411-4
references: 15231648
references: DNA Repair (Amst). 2007 Mar 1;6(3):355-66
references: 17188944
references: Photodermatol Photoimmunol Photomed. 2008 Feb;24(1):2-10
references: 18201350
references: PLoS One. 2010 Aug 10;5(8):e12070
references: 20706593
references: Hum Mutat. 2010 Feb;31(2):159-66
references: 19953527
references: Oncogene. 2013 Sep 19;32(38):4500-8
references: 23108399
references: J Photochem Photobiol A Chem. 2011 Oct 15;224(1):16-24
references: 22081749
references: J Biol Chem. 1992 Jan 5;267(1):166-72
references: 1730583
references: Nucleic Acids Res. 2011 Jul;39(12):5057-66
references: 21398635
references: Science. 2005 Sep 16;309(5742):1871-4
references: 16166520
references: Proc Natl Acad Sci U S A. 2009 Oct 27;106(43):18201-6
references: 19820168
references: DNA Repair (Amst). 2007 Mar 1;6(3):344-54
references: 17188583
references: Nature. 2007 Jun 21;447(7147):941-50
references: 17581577
references: Cancer Res. 2009 May 15;69(10):4372-9
references: 19435918
references: Photochem Photobiol. 2012 Jan-Feb;88(1):5-13
references: 22077233
references: J Biol Chem. 2003 Oct 3;278(40):38121-4
references: 12917422
references: Nat Genet. 2002 Feb;30(2):227-32
references: 11818965
references: IARC Monogr Eval Carcinog Risk Chem Hum. 1981 May;26:1-411
references: 6944253
references: Nat Rev Mol Cell Biol. 2006 May;7(5):335-46
references: 16612326
references: DNA Repair (Amst). 2014 Jan;13:10-21
references: 24315136
references: Mutagenesis. 2011 Jan;26(1):125-32
references: 21164193
references: DNA Repair (Amst). 2008 Dec 1;7(12):1982-9
references: 18793759
references: Cancer Sci. 2011 Apr;102(4):677-82
references: 21235684
references: DNA Repair (Amst). 2010 Jun 4;9(6):700-7
references: 20418187
references: Cancer Res. 1990 Jul 15;50(14):4248-53
references: 2364383
references: J Invest Dermatol. 2014 May;134(5):1408-1417
references: 24284422
references: J Am Acad Dermatol. 2008 May;58(5 Suppl 2):S139-48
references: 18410800