【摘 要】
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The neurodegenerative disease known as ataxia-telangiectasia(A-T)is caused by the absence of the ATM(A-T mutated)protein.A long-standing mystery surrounding
【机 构】
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KeyLaboratoryofAnimalModelsandHumanDiseaseMechanismsofChineseAcademyofSciences&YunnanProvince,Kunmin
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The neurodegenerative disease known as ataxia-telangiectasia(A-T)is caused by the absence of the ATM(A-T mutated)protein.A long-standing mystery surrounding A-T is why cerebellar Purkinje cells(PCs)appear uniquely vulnerable to ATM-deficiency.Here,we present that 5-hydroxymethylcytosine(5hmC),a newly recognized epigenetic marker found at high levels in neurons,is substantially reduced in human A-T and Atm-/-mouse cerebellar PCs.TET1,an enzyme that converts 5mC to 5hmC,responds to DNA damage.Manipulation of TET1 activity directly affects neuronal cell cycle reentry and cell death after the induction of DNA damage.Quantitative,genome-wide analysis of 5hmC of samples from human cerebellum showed that in ATM-deficiency there is a remarkable genome-wide reduction of 5hmC enrichment at both proximal and distal regulatory elements.These results reveal a role of TET1-mediated 5hmC in DNA damage response,and provide insights into the basis of a PC-specific DNA demethylation alteration in ATM-deficiency.
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