X-Message-Number: 30945
Date: Sun, 17 Aug 2008 20:56:42 -0700 (PDT)
From: 
Subject: how to suppress gross chromosomal rearrangements

Proc Natl Acad Sci U S A. 2006 Feb 7;103(6):1816-21. Epub 2006 Jan 30.
Suppression of gross chromosomal rearrangements by yKu70-yKu80 heterodimer
through DNA damage checkpoints.
    Banerjee S, Smith S, Myung K. Genome Instability Section, Genetics and
Molecular Biology Branch, National Human Genome Research Institute, National
Institutes of Health, 49 Convent Drive, Bethesda, MD 20892, USA.
    The inactivation of either subunit of the Ku70-Ku80 heterodimer, which
functions in nonhomologous end-joining and telomere maintenance, generates
severe defects such as sensitivity to DNA damage, telomere shortening, and
increased gross chromosomal rearrangements (GCRs) that are frequently
observed in many cancers. To understand the mechanism of Ku as a genome
gatekeeper, we overexpressed the yKu70-yKu80 heterodimer and monitored the
formation of GCRs. Ku overexpression suppressed the formation of either
spontaneously generated GCRs or those induced by treatments with different
DNA damaging agents. Interestingly, this suppression depended on Ku's
interaction with DNA damage checkpoints and not through nonhomologous
end-joining. We also demonstrate that the inactivation of telomerase
inhibitor, Pif1 along with Ku overexpression or the overexpression of Pif1
in either yku70 or yku80 strains arrested the cell cycle at S phase in a DNA
damage checkpoint-dependent fashion. Lastly, Ku overexpression causes cell
growth delay, which depends on intact Rad27. In summary, the results
presented here suggest that Ku functions as a genomic gatekeeper through its
crosstalk with DNA damage checkpoints.
PMID: 16446442

[Increased gross chromosomal rearrangements leads to accelerated aging in
mice. However this is not the same thing as saying that decreased gross
chromosomal rearrangements would slow aging.]

Cell Cycle. 2008 May;7(9):1139-45. Epub 2008 Feb 22.
Is NHEJ a tumor suppressor or an aging suppressor?
    Hasty P. Department of Molecular Medicine and Institute of
Biotechnology, University of Texas Health Science Center, San Antonio,
Texas, USA.
    Tumor suppressors are longevity assurance genes that ensure early life
fitness. Genes are defined as tumor suppressors if their mutation
predisposes the animal to cancer (a phenotype-based definition). Tumor
suppressors fall into two categories: caretakers and gatekeepers. Caretakers
suppress cancer by repairing damaged DNA while gatekeepers suppress cancer
by halting the cell cycle long enough to repair damaged DNA. If the damage
is irreparable, gatekeepers induce either apoptosis or senescence. These
responses are deleterious to the cell but protect the organism. p53 is the
best-known gatekeeper because it is mutated in over half of all cancers.
Nonhomologous end joining (NHEJ) is considered a caretaker since it repairs
DNA double-strand breaks that would otherwise lead to gross chromosomal
rearrangements (GCRs). NHEJ-mutant mice display increased GCRs, but without
increased cancer. Instead these mice show early aging. This commentary
focuses on the role NHEJ has on aging and cancer. I propose that NHEJ
evolved to reduce GCRs and moderate gatekeeper responses that would
otherwise cause early aging. Furthermore, NHEJ did not evolve to suppress
tumors and any observed tumor suppression is merely circumstantial to
unnatural laboratory conditions coupled with human bias that favors defining
all DNA repair pathways as caretakers.
PMID: 18418036

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