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http://rsx.sagepub.com/ Reproductive Sciences http://rsx.sagepub.com/content/17/11/977.citation The online version of this article can be found at: DOI: 10.1177/1933719110386448 2010 17: 977 Reproductive Sciences Maria 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 Sciences Additional services and information for http://rsx.sagepub.com/cgi/alerts Email Alerts: http://rsx.sagepub.com/subscriptions Subscriptions: http://www.sagepub.com/journalsReprints.nav Reprints: http://www.sagepub.com/journalsPermissions.nav Permissions: What is This? - Oct 12, 2010 Version of Record >> at Middle East Technical Univ on May 20, 2014 rsx.sagepub.com Downloaded from at Middle East Technical Univ on May 20, 2014 rsx.sagepub.com Downloaded from

A Better Understanding of BRCA2 Function

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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

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