DNA Repair

Publication Title: 
Nature

XPF-ERCC1 endonuclease is required for repair of helix-distorting DNA lesions and cytotoxic DNA interstrand crosslinks. Mild mutations in XPF cause the cancer-prone syndrome xeroderma pigmentosum. A patient presented with a severe XPF mutation leading to profound crosslink sensitivity and dramatic progeroid symptoms. It is not known how unrepaired DNA damage accelerates ageing or its relevance to natural ageing. Here we show a highly significant correlation between the liver transcriptome of old mice and a mouse model of this progeroid syndrome.

Author(s): 
Niedernhofer, Laura J.
Garinis, George A.
Raams, Anja
Lalai, Astrid S.
Robinson, Andria Rasile
Appeldoorn, Esther
Odijk, Hanny
Oostendorp, Roos
Ahmad, Anwaar
van Leeuwen, Wibeke
Theil, Arjan F.
Vermeulen, Wim
van der Horst, Gijsbertus T. J.
Meinecke, Peter
Kleijer, Wim J.
Vijg, Jan
Jaspers, Nicolaas G. J.
Hoeijmakers, Jan H. J.
Publication Title: 
Journal of Biochemistry

FOXO (Forkhead box O) transcription factors constitute an evolutionally conserved subgroup within the large Forkhead family of transcription regulators. FOXO factors are important regulators of the cell cycle, apoptosis, DNA repair, metabolism, oxidative stress resistance and longevity. Genetic studies of Caenorhabditis elegans demonstrated that FOXO factors are major targets of the insulin-like signalling implicated during the regulation of glucose metabolism and lifespan extension.

Author(s): 
Daitoku, Hiroaki
Fukamizu, Akiyoshi
Publication Title: 
Nature Communications

With ageing, there is a loss of adult stem cell function. However, there is no direct evidence that this has a causal role in ageing-related decline. We tested this using muscle-derived stem/progenitor cells (MDSPCs) in a murine progeria model. Here we show that MDSPCs from old and progeroid mice are defective in proliferation and multilineage differentiation. Intraperitoneal administration of MDSPCs, isolated from young wild-type mice, to progeroid mice confer significant lifespan and healthspan extension.

Author(s): 
Lavasani, Mitra
Robinson, Andria R.
Lu, Aiping
Song, Minjung
Feduska, Joseph M.
Ahani, Bahar
Tilstra, Jeremy S.
Feldman, Chelsea H.
Robbins, Paul D.
Niedernhofer, Laura J.
Huard, Johnny
Publication Title: 
Molecular Aspects of Medicine

Poly(ADP-ribosyl)ation (PARylation) is a posttranslational protein modification (PTM) catalyzed by members of the poly(ADP-ribose) polymerase (PARP) enzyme family. PARPs use NAD(+) as substrate and upon cleaving off nicotinamide they transfer the ADP-ribosyl moiety covalently to suitable acceptor proteins and elongate the chain by adding further ADP-ribose units to create a branched polymer, termed poly(ADP-ribose) (PAR), which is rapidly degraded by poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribosylhydrolase 3 (ARH3).

Author(s): 
B¸rkle, Alexander
Vir·g, L·szlÛ
Publication Title: 
Free Radical Biology & Medicine

The consequence of decreased nicotinamide adenine dinucleotide (NAD(+)) levels as a result of oxidative challenge is altered activity of sirtuins, which, in turn, brings about a wide range of modifications in mammalian cellular metabolism. Sirtuins, especially SIRT1, deacetylate important transcription factors such as p53, forkhead homeobox type O proteins, nuclear factor ?B, or peroxisome proliferator-activated receptor ? coactivator 1? (which controls the transcription of pro- and antioxidant enzymes, by which the cellular redox state is affected).

Author(s): 
Radak, Zsolt
Koltai, Erika
Taylor, Albert W.
Higuchi, Mitsuru
Kumagai, Shuzo
Ohno, Hideki
Goto, Sataro
Boldogh, Istvan
Publication Title: 
Annual Review of Physiology

Genome instability has long been implicated as the main causal factor in aging. Somatic cells are continuously exposed to various sources of DNA damage, from reactive oxygen species to UV radiation to environmental mutagens. To cope with the tens of thousands of chemical lesions introduced into the genome of a typical cell each day, a complex network of genome maintenance systems acts to remove damage and restore the correct base pair sequence.

Author(s): 
Vijg, Jan
Suh, Yousin
Publication Title: 
Mechanisms of Ageing and Development

Cockayne syndrome (CS) is a rare multisystem disorder characterized by cachectic dwarfism, nervous system abnormalities and features of premature aging. CS symptoms are associated with mutations in 5 genes, CSA, CSB, XPB, XPD and XPG encoding for proteins involved in the transcription-coupled subpathway of nucleotide excision DNA repair (NER). Mutant mice have been generated for all CS-associated genes and provide tools to examine how the cellular defects translate into CS symptoms.

Author(s): 
Jaarsma, Dick
van der Pluijm, Ingrid
van der Horst, Gijsbertus T. J.
Hoeijmakers, Jan H. J.
Publication Title: 
Nature Communications

It is hypothesized that a common underlying mechanism links multiple neurodegenerative disorders. Here we show that transitional endoplasmic reticulum ATPase (TERA)/valosin-containing protein (VCP)/p97 directly binds to multiple polyglutamine disease proteins (huntingtin, ataxin-1, ataxin-7 and androgen receptor) via polyglutamine sequence. Although normal and mutant polyglutamine proteins interact with TERA/VCP/p97, only mutant proteins affect dynamism of TERA/VCP/p97.

Author(s): 
Fujita, Kyota
Nakamura, Yoko
Oka, Tsutomu
Ito, Hikaru
Tamura, Takuya
Tagawa, Kazuhiko
Sasabe, Toshikazu
Katsuta, Asuka
Motoki, Kazumi
Shiwaku, Hiroki
Sone, Masaki
Yoshida, Chisato
Katsuno, Masahisa
Eishi, Yoshinobu
Murata, Miho
Taylor, J. Paul
Wanker, Erich E.
Kono, Kazuteru
Tashiro, Satoshi
Sobue, Gen
La Spada, Albert R.
Okazawa, Hitoshi
Publication Title: 
Molecules and Cells

Sirtuins (SIRTs), a family of nicotinamide adenine dinucleotide (NAD)-dependent deacetylases, are emerging as key molecules that regulate aging and age-related diseases including cancers, metabolic disorders, and neurodegenerative diseases. Seven isoforms of SIRT (SIRT1-7) have been identified in mammals. SIRT1 and 6, mainly localized in the nucleus, regulate transcription of genes and DNA repair. SIRT3 in the mitochondria regulates mitochondrial bioenergetics.

Author(s): 
Park, Seongjoon
Mori, Ryoichi
Shimokawa, Isao
Publication Title: 
Nature Communications

A de novo G608G mutation in LMNA gene leads to Hutchinson-Gilford progeria syndrome. Mice lacking the prelamin A-processing metalloprotease, Zmpste24, recapitulate many of the progeroid features of Hutchinson-Gilford progeria syndrome. Here we show that A-type lamins interact with SUV39H1, and prelamin A/progerin exhibits enhanced binding capacity to SUV39H1, protecting it from proteasomal degradation and, consequently, increasing H3K9me3 levels. Depletion of Suv39h1 reduces H3K9me3 levels, restores DNA repair capacity and delays senescence in progeroid cells.

Author(s): 
Liu, Baohua
Wang, Zimei
Zhang, Le
Ghosh, Shrestha
Zheng, Huiling
Zhou, Zhongjun

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