Diminished Telomeric 3′ Overhangs Are Associated with Telomere Dysfunction in Hoyeraal-Hreidarsson Syndrome 英文参考文献.docVIP

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Diminished Telomeric 3′ Overhangs Are Associated with Telomere Dysfunction in Hoyeraal-Hreidarsson Syndrome 英文参考文献.doc

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Diminished Telomeric 3′ Overhangs Are Associated with Telomere Dysfunction in Hoyeraal-Hreidarsson Syndrome 英文参考文献

DiminishedTelomeric39OverhangsAreAssociatedwith TelomereDysfunctioninHoyeraal-Hreidarsson Syndrome NoaLamm1,EllyOrdan1,3,RotemShponkin1,CarmelitRichler1,MemetAker2,YehudaTzfati1* 1Department of Genetics, The Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram, Jerusalem, Israel, 2Department of Pediatric Hematology-Oncology,HadassahUniversityHospital,EinKerem,Jerusalem,Israel,3DepartmentofBiochemistry,TheHebrewUniversity-HadassahMedicalSchool,Ein Kerem,Jerusalem,Israel Abstract Background:Eukaryoticchromosomesendwithtelomeres,whichinmostorganismsarecomposedoftandemDNArepeats associatedwithtelomericproteins.TheseDNArepeatsaresynthesizedbytheenzymetelomerase,whoseactivityinmost humantissuesistightlyregulated,leadingtogradualtelomereshorteningwithcelldivisions.Shorteningbeyondacritical lengthcausestelomereuncapping,manifestedbytheactivationofaDNAdamageresponse(DDR)andconsequentlycell cycle arrest. Thus, telomere length limits the number of cell divisions and provides a tumor-suppressing mechanism. However,notonlytelomereshortening,butalsodamagedtelomerestructure,cancausetelomereuncapping.Dyskeratosis Congenita (DC) and its severe form Hoyeraal-Hreidarsson Syndrome (HHS) are genetic disorders mainly characterized by telomerase deficiency, accelerated telomere shortening, impaired cell proliferation, bone marrow failure, and immunodeficiency. Methodology/PrincipalFindings:WestudiedthetelomerephenotypesinafamilyaffectedwithHHS,inwhichthegenes implicatedinothercasesofDCandHHShavebeenexcluded,andtelomeraseexpressionandactivityappearstobenormal. Telomeresinbloodleukocytesderivedfromthepatientswereseverelyshort,butinprimaryfibroblaststheywerenormalin length.Nevertheless,asignificantfractionoftelomeresinthesefibroblastsactivatedDDR,anindicationoftheiruncapped state. In addition, the telomeric 39 overhangs are diminished in blood cells and fibroblasts derived from the patients, consistentwithadefectintelomerestructurecommontobothcelltypes. C