EMERGING ROLES FOR THE RB-PATHWAY IN DNA REPLICATION CONTROL

 
 
 
 

EMERGING ROLES FOR THE RB-PATHWAY IN DNA REPLICATION CONTROL

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Title: EMERGING ROLES FOR THE RB-PATHWAY IN DNA REPLICATION CONTROL
Author: BRADEN, WESLEY A
Description: The retinoblastoma tumor suppressor (RB) pathway is disrupted in over 70% of human cancers. As such, understanding the molecular mechanisms by which the RB-pathway contributes to cancer development is an area of intense study. RB is functionally inactivated either by gene mutation, enhanced degradation by DNA tumor viruses, loss of p16ink4a, or amplification of cyclin D1. This inactivation of RB leads to the disruption of the cell cycle at the G1-S phase boundary, promoting uncontrolled DNA synthesis and cell division. While RB is known to regulate genes necessary for S-phase entry, the role of the RB-pathway in regulating DNA replication is less well understood. Here provide evidence that the RB-pathway controls DNA replication at two distinct points in the cell cycle. First, p16ink4a inhibits the pre-replicative complex (pre-RC) in G1 phase, while RB represses DNA replication in S-phase. Specifically, we demonstrate that CDK4 kinase activity promotes pre-RC assembly as cells exit mitosis and enter G1, and that CDK4 inhibition, either by p16ink4a or drug targeting, results in the cessation of pre-RC formation. Conversely, CDK2 inhibition via RB expression or drug targeting prevents the completion of DNA replication in S-phase. In addition, we find that a functional RB-pathway is required for CDK4 inhibition to influence replication control. CDK4 signals through RB to elicit transcriptional repression of CDK2, suggesting both kinases play an important role in DNA replication. Interestingly, while CDK2 inhibition alone was insufficient to disrupt the pre-RC, cells lacking D-type cyclins are sensitized to CDK2-mediated pre-RC inhibition. Together, these results demonstrate a novel role for the RB-pathway in regulating the initiation of DNA replication, as well as the maintenance of the replisome.
Permanent Link: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1195228828
http://hdl.handle.net/2374.OX/12095
Date: 2007

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