Yeast Nhp6A/B and mammalian Hmgb1 facilitate the maintenance of genome stability.
Saccharomyces cerevisiae Nhp6A and Nhp6B are chromatin architectural factors that belong to the high-mobility group box (HMGB) superfamily and appear to be functionally related to mammalian Hmgb1. They bind to the minor groove of double-stranded DNA in a non-sequence-specific manner and thereby influence chromatin structure. Previous work has implicated these proteins in a variety of nuclear processes, including chromatin remodeling, DNA replication, transcription, and recombination . Here, we show that Nhp6A/B loss leads to increased genomic instability, hypersensitivity to DNA-damaging agents, and shortened yeast cell life span that is associated with elevated levels of extrachromosomal rDNA circles. Furthermore, we show that hypersensitivity toward UV light does not appear to reflect a decreased capacity for DNA repair but instead correlates with higher levels of UV-induced thymine dimer adducts being formed in cells lacking Nhp6A/B. Likewise, we show that mouse fibroblasts lacking Hmgb1 display higher rates of damage after UV irradiation than wild-type controls and also exhibit pronounced chromosomal instability. Taken together, these data indicate that Nhp6A/B and Hmgb1 protect DNA from damaging agents and thus guard against the generation of genomic aberrations.
Giavara
Sabrina
S
The Wellcome Trust and Cancer Research UK Gurdon Institute and Department of Zoology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, United Kingdom.
Kosmidou
Effie
E
Hande
M Prakash
MP
Bianchi
Marco E
ME
Morgan
Alan
A
d'Adda di Fagagna
Fabrizio
F
Jackson
Stephen P
SP
D000818:Animals; D002843:Chromatin / Q000378:metabolism* / Q000502:physiology; D018736:DNA Adducts / Q000502:physiology; D004249:DNA Damage / Q000502:physiology; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000528:radiation effects; D042822:Genomic Instability / Q000235:genetics / Q000502:physiology*; D024243:HMGB1 Protein / Q000378:metabolism*; D024001:HMGN Proteins; D008136:Longevity; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D011740:Pyrimidine Dimers / Q000528:radiation effects; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D014466:Ultraviolet Rays
D002843:Chromatin; D018736:DNA Adducts; D004268:DNA-Binding Proteins; D024243:HMGB1 Protein; D024001:HMGN Proteins; C086471:NHP6A protein, S cerevisiae; C086472:NHP6B protein, S cerevisiae; D009687:Nuclear Proteins; D011740:Pyrimidine Dimers; D029701:Saccharomyces cerevisiae Proteins