Genomic Instability

Publication Title: 
Blood

To obtain the large amount of T cells required for adoptive immunotherapy in a clinical setting, T-cell lifespan extension by human telomerase reverse transcriptase (hTERT) transduction is of particular interest. However, constitutive expression of hTERT is associated with malignant transformation and thus warrants a detailed evaluation of the safety of hTERT-transduced T cells before clinical application.

Author(s): 
Schreurs, Marco W. J.
Hermsen, Mario A. J. A.
Geltink, Ramon I. Klein
Scholten, Kirsten B. J.
Brink, Antoinette A. T. P.
Kueter, Esther W. M.
Tijssen, Marianne
Meijer, Chris J. L. M.
Ylstra, Bauke
Meijer, Gerrit A.
Hooijberg, Erik
Publication Title: 
Mechanisms of Ageing and Development

In his pleasantly provocative opinion paper, Aubrey de Grey's argues that (a) independent age-related deteriorative processes evolve to reach approximately equal importance for the aging process as a whole, but (b) this equality can be broken by "protagonistic pleiotropies", i.e. when a process is contributing to more than one competing death causes. In particular, the fact that nDNA mutations are extremely efficient in killing by inducing cancer implies that these mutations should be irrelevant for non-cancer aging.

Author(s): 
Khrapko, Konstantin
Publication Title: 
Medical Hypotheses

Many mechanisms contribute to senescence, such as telomere shortening in replicative cells, cumulative damage to DNA leading to genomic instability, and oxidative damage to molecules by reactive oxygen species (ROS). These include chronic low-grade inflammation (inflammageing), a major risk factor for ageing and age-related diseases, such as Alzheimer's disease and type II diabetes. Furthermore, the prevention of inflammageing seems to be one of the most effective approaches to increase longevity.

Author(s): 
Matsumoto, Mitsuharu
Kurihara, Shin
Publication Title: 
Nature

The naked mole rat (Heterocephalus glaber) is a strictly subterranean, extraordinarily long-lived eusocial mammal. Although it is the size of a mouse, its maximum lifespan exceeds 30 years, making this animal the longest-living rodent. Naked mole rats show negligible senescence, no age-related increase in mortality, and high fecundity until death. In addition to delayed ageing, they are resistant to both spontaneous cancer and experimentally induced tumorigenesis. Naked mole rats pose a challenge to the theories that link ageing, cancer and redox homeostasis.

Author(s): 
Kim, Eun Bae
Fang, Xiaodong
Fushan, Alexey A.
Huang, Zhiyong
Lobanov, Alexei V.
Han, Lijuan
Marino, Stefano M.
Sun, Xiaoqing
Turanov, Anton A.
Yang, Pengcheng
Yim, Sun Hee
Zhao, Xiang
Kasaikina, Marina V.
Stoletzki, Nina
Peng, Chunfang
Polak, Paz
Xiong, Zhiqiang
Kiezun, Adam
Zhu, Yabing
Chen, Yuanxin
Kryukov, Gregory V.
Zhang, Qiang
Peshkin, Leonid
Yang, Lan
Bronson, Roderick T.
Buffenstein, Rochelle
Wang, Bo
Han, Changlei
Li, Qiye
Chen, Li
Zhao, Wei
Sunyaev, Shamil R.
Park, Thomas J.
Zhang, Guojie
Wang, Jun
Gladyshev, Vadim N.
Publication Title: 
Oncogene

Mitochondrial dysfunction has been a hallmark of cancer. However, whether it has a causative role awaits to be elucidated. Here, using an animal model derived from inactivation of SUV3, a mitochondrial helicase, we demonstrated that mSuv3+/- mice harbored increased mitochondrial DNA (mtDNA) mutations and decreased mtDNA copy numbers, leading to tumor development in various sites and shortened lifespan. These phenotypes were transmitted maternally, indicating the etiological role of the mitochondria.

Author(s): 
Chen, P.-L.
Chen, C.-F.
Chen, Y.
Guo, X. E.
Huang, C.-K.
Shew, J.-Y.
Reddick, R. L.
Wallace, D. C.
Lee, W.-H.
Publication Title: 
Rejuvenation Research

Methylation of DNA is intimately involved in control of mammalian/vertebrate gene expression as part of a complex epigenetic regulatory system. We hypothesize that DNA methylation at cytosine-phosphate-guanine sites (CpGs), the "DNA methylome," evolved to increase stability of the differentiated state in somatic vertebrate cells, especially post-mitotic cells, which may have helped to increase longevity. Therefore, the DNA methylome may play a key role in human aging and be an ideal source of biomarkers aging.

Author(s): 
Mendelsohn, Andrew R.
Larrick, James W.
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: 
Biochemistry. Biokhimii?a

The processes that lead to violation of genome integrity are known to increase with age. This phenomenon is caused both by increased production of reactive oxygen species and a decline in the efficiency of antioxidant defense system as well as systems maintaining genome stability. Accumulation of different unrepairable genome damage with age may be the cause of many age-related diseases and the development of phenotypic and physiological signs of aging.

Author(s): 
Shilovsky, G. A.
Khokhlov, A. N.
Shram, S. I.
Publication Title: 
Molecular and Cellular Biology

The DNA damage response (DDR) is critical for genome stability and the suppression of a wide variety of human malignancies, including neurodevelopmental disorders, immunodeficiency, and cancer. In addition, the efficacy of many chemotherapeutic strategies is dictated by the status of the DDR. Ubiquitin-specific protease 28 (USP28) was reported to govern the stability of multiple factors that are critical for diverse aspects of the DDR. Here, we examined the effects of USP28 depletion on the DDR in cells and in vivo.

Author(s): 
Knobel, Philip A.
Belotserkovskaya, Rimma
Galanty, Yaron
Schmidt, Christine K.
Jackson, Stephen P.
Stracker, Travis H.
Publication Title: 
PloS One

The chronological lifespan of eukaryotic organisms is extended by the mutational inactivation of conserved growth-signaling pathways that regulate progression into and through the cell cycle. Here we show that in the budding yeast S. cerevisiae, these and other lifespan-extending conditions, including caloric restriction and osmotic stress, increase the efficiency with which nutrient-depleted cells establish or maintain a cell cycle arrest in G1.

Author(s): 
Weinberger, Martin
Feng, Li
Paul, Anita
Smith, Daniel L.
Hontz, Robert D.
Smith, Jeffrey S.
Vujcic, Marija
Singh, Keshav K.
Huberman, Joel A.
Burhans, William C.

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