Human HLTF functions as a ubiquitin ligase for proliferating cell nuclear antigen polyubiquitination.
Human helicase-like transcription factor (HLTF) is frequently inactivated in colorectal and gastric cancers. Here, we show that HLTF is a functional homologue of yeast Rad5 that promotes error-free replication through DNA lesions. HLTF and Rad5 share the same unique structural features, including a RING domain embedded within a SWI/SNF helicase domain and an HIRAN domain. We find that inactivation of HLTF renders human cells sensitive to UV and other DNA-damaging agents and that HLTF complements the UV sensitivity of a rad5Delta yeast strain. Also, similar to Rad5, HLTF physically interacts with the Rad6-Rad18 and Mms2-Ubc13 ubiquitin-conjugating enzyme complexes and promotes the Lys-63-linked polyubiquitination of proliferating cell nuclear antigen at its Lys-164 residue. A requirement of HLTF for error-free postreplication repair of damaged DNA is in keeping with its cancer-suppression role.
Unk
Ildiko
I
Institute of Genetics, Biological Research Center, Hungarian Academy of Sciences, Temesvari Körút 62, H-6726, Szeged, Hungary.
Hajdú
Ildikó
I
Fátyol
Károly
K
Hurwitz
Jerard
J
Yoon
Jung-Hoon
JH
Prakash
Louise
L
Prakash
Satya
S
Haracska
Lajos
L
D000251:Adenosine Triphosphatases / Q000378:metabolism; D002460:Cell Line; D004265:DNA Helicases; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004351:Drug Resistance / Q000187:drug effects / Q000528:radiation effects; D005816:Genetic Complementation Test; D006801:Humans; D008025:Ligases / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D025821:Polyubiquitin / Q000378:metabolism*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000528:radiation effects; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects / Q000528:radiation effects; D014466:Ultraviolet Rays
D004268:DNA-Binding Proteins; C100023:HLTF protein, human; D018809:Proliferating Cell Nuclear Antigen; C485954:RAD18 protein, human; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D025821:Polyubiquitin; D008741:Methyl Methanesulfonate; C471607:UBE2N protein, human; C114715:UBE2V2 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases; D000251:Adenosine Triphosphatases; C076225:RAD5 protein, S cerevisiae; D004265:DNA Helicases; D008025:Ligases; D008239:Lysine