Upload
m-r
View
218
Download
2
Embed Size (px)
Citation preview
http://rsx.sagepub.com/Reproductive Sciences
http://rsx.sagepub.com/content/17/11/977.citationThe online version of this article can be found at:
DOI: 10.1177/1933719110386448
2010 17: 977Reproductive SciencesMaria Rosa Maduro
A Better Understanding of BRCA2 Function
Published by:
http://www.sagepublications.com
On behalf of:
Society for Gynecologic Investigation
can be found at:Reproductive SciencesAdditional services and information for
http://rsx.sagepub.com/cgi/alertsEmail Alerts:
http://rsx.sagepub.com/subscriptionsSubscriptions:
http://www.sagepub.com/journalsReprints.navReprints:
http://www.sagepub.com/journalsPermissions.navPermissions:
What is This?
- Oct 12, 2010Version of Record >>
at Middle East Technical Univ on May 20, 2014rsx.sagepub.comDownloaded from at Middle East Technical Univ on May 20, 2014rsx.sagepub.comDownloaded from
In the Spotlight
A Better Understandingof BRCA2 Function
Maria Rosa Maduro, PhD
Mutations in the breast cancer susceptibility gene BRCA2 are
well known to result in chromosomal instability characterized
by an accumulation of chromosomal breaks, translocations,
exchanges, and other abnormal structures that constitute a hall-
mark of tumorigenesis. Accordingly, these mutations are also
associated with a high incidence of breast and ovarian cancer,
as well as tumors in other tissues and organs.
For these reasons, a mechanistic insight into how BRCA2
functions has long been sought for, as it would open a whole new
venue to better understand these devastating diseases. However,
its large size (the human protein comprises 3418 amino acids),
the difficulty in achieving high-level expression, its insufficient
solubility, and its propensity to degrade have precluded isolation
of the full-length BRCA2 protein and, therefore, hampered all
the attempts to further know how it functions.
Thus, a recent report by Jensen et al in the journal Nature
(Nat., ahead of print, published online August 22, 2010)
describing not only the purification of the full-length BRAC2
from human cells but also its biochemical functions with regard
to recombinational DNA repair was distinctively received.
Jensen and colleagues report that BRCA2 stimulates the
functions of RAD51 that are essential for recombinational
repair of DNA breaks. They have shown that BRAC2 enforces
RAD51 binding to single-stranded DNA (ssDNA), accelerates
the rate of the replication protein A (RPA) displacement from
ssDNA by RAD51 and inhibits the ATPase activity of RAD51
stabilizing the RAD51-ssDNA filaments. In addition, the
authors observed that BRCA2 prevents or slows the assembly
of RAD51 onto duplex DNA, impairing recombination reac-
tions with double-stranded DNA (dsDNA). Finally, Jensen and
colleagues show that BRCA2 does not anneal ssDNA com-
plexed with RPA, implying that it does not directly function
in repair processes that involve ssDNA annealing.
Altogether, the work presented by Jensen et al has confirmed
and extended prior expectations to the human BRAC2, helping
explaining why cells lacking a functional BRCA2 would be
severely impaired in the formation of critical structural inter-
mediates of recombinational repair, consequently disrupting
template-directed repair from homologous sequences and leading
to error prone repair and chromosomal instability. These findings
are certainly critical to achieve further knowledge on an impor-
tant protein, which when defective is directly responsible to
genetically predispose individuals to cancer development.
New Genes Involved in OvarianClear Cell Carcinoma
Ovarian cancer is one of the most common gynecologic malig-
nancies, presenting with a high mortality rate, due to the fact
that it usually goes unnoticed in its earlier stages and only
becomes diagnosed at a later stage when the disease is already
widespread. Ovarian clear cell carcinoma (OCCC) is a partic-
ularly aggressive form of ovarian cancer that is commonly
resistant to therapy and, therefore, usually presents with a
poorer prognosis.
Thus, the identification of biomarkers that would allow the
screening of individuals at risk of OCCC and that would enable
the development of new and more efficient therapies for the
disease is greatly needed.
Appropriately, Jones et al have just reported in the journal
Science (Science Express, published online September 8,
2010) the identification of new genes previously unrecognized
to be strongly associated with OCCC.
In their study, Jones and colleagues started out by purifying
OCCC cancer cells through immunoaffinity and then deter-
mined the exomic sequences of 8 tumors. Through comparative
analyses of normal cells from the same patients, the authors
were able to identify 4 genes that were mutated in at least 2
tumors. From these, 2 had previously been implicated in
OCCC: PIK3CA, which encodes a subunit of phosphatidylino-
sitol 3 kinase, and KRAS, which encodes an oncoprotein. The
other 2 genes had never been associated with OCCC. One of
them is PPP2R1A, which encodes a regulatory subunit of a ser-
ine/threonine phosphatase 2, and that seems to function has an
oncogene. The other one is ARID1A, which encodes an AT-rich
interactive domain-containing protein 1A that is involved in
chromatin remodeling and seems to act as a tumor suppressor
gene.
Impressively, ARID1A mutations were present in as much as
57% of the OCCCs, and PPP2R1A mutations were detected in
7% of them.
In sum, the work presented by Jones et al suggests that
abnormal chromatin remodeling is involved in OCCC develop-
ment. Moreover, it presents new candidate genes for OCCC
screening of individuals at risk and provides a better under-
standing of the disease, opening the doors to the development
of new therapeutic strategies.
Reproductive Sciences17(11) 977ª The Author(s) 2010Reprints and permission:sagepub.com/journalsPermissions.navDOI: 10.1177/1933719110386448http://rs.sagepub.com
at Middle East Technical Univ on May 20, 2014rsx.sagepub.comDownloaded from