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. 1. General Information on Tousled-Like Kinases The Tousled locus was originally identified in A. thaliana and Antirrhinum majus during a study of mutations leading to defects in meristem expansion. Mutations of Tousled produce a complex phenotype characterized by specific defects in development of leaf and floral organs [1]. This was proposed to be linked to a replicative defect during organogenesis, but it may also result from failure to protect the genomefrom DNA damage [2, 3], resulting in developmental aberrations [4, 5]. Highly related Tousled-like genes can be found in many organisms in both kingdoms, several of which encode multiple transcripts resulting in different protein isoforms [6]. It was originally proposed that Tousled (TSL) may be a component in a signal transduction pathway controlling cell proliferation and DNA synthesis during organogenesis, and this immediately prompted a search for its substrates. However, unlike most kinases that usually display a propensity to phosphorylate numerous substrates, after many years of study, only a few direct “interacting” substrates of TLKs have been identified, namely, the histone chaperone Asf1 [7], histone H3-S10 [8], Aurora B [5], and more recently Rad9 [9]. This suggested a function for TLKs in chromatin assembly [9, 10], during transcription [2, 11], DNA repair [3, 9, 12], and condensation of chromosomes at mitosis [4, 5]. The latter function, which was found critical for proper chromosome segregation, prompted a search for additional “indirect” substrates and functions and resulted in the identification of an activity on myosin II in mammalian cells [13] and on
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