RECQL4, the protein mutated in Rothmund-Thomson syndrome, functions in telomere maintenance.
Telomeres are structures at the ends of chromosomes and are composed of long tracks of short tandem repeat DNA sequences bound by a unique set of proteins (shelterin). Telomeric DNA is believed to form G-quadruplex and D-loop structures, which presents a challenge to the DNA replication and repair machinery. Although the RecQ helicases WRN and BLM are implicated in the resolution of telomeric secondary structures, very little is known about RECQL4, the RecQ helicase mutated in Rothmund-Thomson syndrome (RTS). Here, we report that RTS patient cells have elevated levels of fragile telomeric ends and that RECQL4-depleted human cells accumulate fragile sites, sister chromosome exchanges, and double strand breaks at telomeric sites. Further, RECQL4 localizes to telomeres and associates with shelterin proteins TRF1 and TRF2. Using recombinant proteins we showed that RECQL4 resolves telomeric D-loop structures with the help of shelterin proteins TRF1, TRF2, and POT1. We also found a novel functional synergistic interaction of this protein with WRN during D-loop unwinding. These data implicate RECQL4 in telomere maintenance.
Laboratory of Molecular Gerontology, Biomedical Research Center, NIA, National Institutes of Health, Baltimore, Maryland 21224.
Avik K
AK
Ghosh
Laboratory of Molecular Gerontology, Biomedical Research Center, NIA, National Institutes of Health, Baltimore, Maryland 21224.
Marie L
ML
Rossi
Laboratory of Molecular Gerontology, Biomedical Research Center, NIA, National Institutes of Health, Baltimore, Maryland 21224.
Dharmendra Kumar
DK
Singh
Laboratory of Molecular Gerontology, Biomedical Research Center, NIA, National Institutes of Health, Baltimore, Maryland 21224.
Christopher
C
Dunn
Laboratory of Molecular Gerontology, Biomedical Research Center, NIA, National Institutes of Health, Baltimore, Maryland 21224.
Mahesh
M
Ramamoorthy
Laboratory of Molecular Gerontology, Biomedical Research Center, NIA, National Institutes of Health, Baltimore, Maryland 21224.
Deborah L
DL
Croteau
Laboratory of Molecular Gerontology, Biomedical Research Center, NIA, National Institutes of Health, Baltimore, Maryland 21224.
Yie
Y
Liu
Laboratory of Molecular Gerontology, Biomedical Research Center, NIA, National Institutes of Health, Baltimore, Maryland 21224. Electronic address: vbohr@nih.gov.
Vilhelm A
VA
Bohr
D016590:Aphidicolin / Q000494:pharmacology; D001483:Base Sequence; D004247:DNA / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects; D005090:Exodeoxyribonucleases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009690:Nucleic Acid Conformation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D053484:RecQ Helicases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011038:Rothmund-Thomson Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016615:Telomere / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1; D000071657:Werner Syndrome Helicase
D047908:Intracellular Signaling Peptides and Proteins; D050505:Mutant Proteins; D034741:RNA, Small Interfering; C498301:TP53BP1 protein, human; D035341:Telomeric Repeat Binding Protein 2; D000071857:Tumor Suppressor p53-Binding Protein 1; D016590:Aphidicolin; D004247:DNA; D005090:Exodeoxyribonucleases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase