The Tousled-Like Kinases as Guardians of Genome Integrity

Arrigo De Benedetti

doi:10.5402/2012/627596

Abstract

The Tousled-like kinases (TLKs) function in processes of chromatin assembly, including replication, transcription, repair, and chromosome segregation. TLKs interact specifically (and phosphorylate) with the chromatin assembly factor Asf1, a histone H3-H4 chaperone, histone H3 itself at Ser10, and also Rad9, a key protein involved in DNA repair and cell cycle signaling following DNA damage. These interactions are believed to be responsible for the action of TLKs in double-stranded break repair and radioprotection and also in the propagation of the DNA damage response. Hence, I propose that TLKs play key roles in maintenance of genome integrity in many organisms of both kingdoms. In this paper, I highlight key issues of the known roles of these proteins, particularly in the context of DNA repair (IR and UV), their possible relevance to genome integrity and cancer development, and as possible targets for intervention in cancer management.

Highlights

The Tousled locus was originally identified in A. thaliana and Antirrhinum majus during a study of mutations leading to defects in meristem expansion
We showed that TLK1B phosphorylates Rad9 at S328 and that this appears to play a key role in resumption of the cell cycle arrested after IR
The most logical conclusion arising from these results, and from the specific pattern of activity of Tousled-like kinases (TLKs), is that the S328 phosphorylation of Rad9 by TLKs is critical for deactivation of the DNA damage response (DDR) checkpoint following DNA repair

Summary

Introduction

The Tousled locus was originally identified in A. thaliana and Antirrhinum majus during a study of mutations leading to defects in meristem expansion. The most logical conclusion arising from these results, and from the specific pattern of activity of TLKs (see below), is that the S328 phosphorylation of Rad9 by TLKs is critical for deactivation of the DDR checkpoint following DNA repair.

Results

Conclusion