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Thursday, April 17, 2008

Journal : Phosphorylation for break repair

Published online 14 April 2008
The Journal of Cell Biology
© The Rockefeller University Press, 0021-9525 $30.00

Phosphorylation for break repair

The retention of MRN (red) at dsDNA breaks (green) is lost when MDC1 phosphorylation sites are mutated (right).

A constitutive, phosphate-based interaction between two repair proteins may help provide instant, well-coordinated repair of double-stranded DNA (dsDNA) breaks, according to two articles in this issue from Melander et al. and Spycher et al.

Nearly every step in dsDNA break repair requires MRN, from recognizing the break to activating signaling pathways to the mechanics of repair—or apoptosis, if repair fails. MRN can bind directly to DNA, but past experiments revealed that it also associates with the histones wrapped around damaged sequences, through an adaptor protein called MDC1.

Both groups now dissect this chromatin association. The findings reveal that the connection depends on a heavily phosphorylated domain within MDC1, which docks to a subunit of MRN called NBS1. In both articles, MRN was displaced from dsDNA breaks in cells containing mutant versions of MDC1 that lacked the phosphorylation sites.

The link between MRN and MDC1 did not depend on the presence of damaged DNA, however; even undamaged cells had phosphorylated MDC1. This phosphorylation depended at least in part on the constitutive and ubiquitous kinase, casein kinase 2 (CK2). Depletion of CK2 blocked the interaction between the repair proteins.

Repair aficionados often think that events taking place on the DNA itself are more important. But cells spend a great deal of energy coordinating the comings and goings of repair proteins on the chromatin, suggesting that these events might have evolved to improve repair precision. MDC1 is one of the earliest proteins to recognize histones at damage sites; by forming a constitutive link with MDC1, MRN ensures a rapid arrival to those same sites.

Previous results showed that MDC1 stays on damaged chromatin longer than MRN, indicating that the MDC1-MRN link is dynamic. This freedom may allow MRN to travel from the damage to the sundry other sites where it is needed, including the broken ends of the DNA.

The groups now hope to uncouple MRN and MDC1 without interfering with MDC1’s other binding partners by mutating only its CK2 target sites. They can then determine which of MRN’s sundry repair duties rely on its association with chromatin.

Melander, F., et al. 2008. J. Cell Biol. doi:10.1083/jcb.200708210. [Abstract]

Spycher, C., et al. 2008. J. Cell Biol. doi:10.1083/jcb.200709008. [Abstract]

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