Differential regulation of the PIKK kinase family by Tel2

Boulton, Simon J.

doi:10.4161/cc.7.23.7430

Cited by 1 publication

(1 citation statement)

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“…The stability/assembly of PIKKs is influenced by the interaction of RuvBL1-RuvBL2 with Tel2/hCLK2 and Hsp90 ( 68 – 72 ). Neither knockdown of Tel2 by siRNA, nor inhibition of Hsp90 by 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) alters the global abundance of the FA core complex (Figure 4A and Supplementary Figures S8A and S9).…”

Section: Resultsmentioning

confidence: 99%

Abundance of the Fanconi anaemia core complex is regulated by the RuvBL1 and RuvBL2 AAA+ ATPases

Rajendra

Garaycoechea

Patel

et al. 2014

Nucleic Acids Research

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Fanconi anaemia (FA) is a genome instability disease caused by defects in the FA DNA repair pathway that senses and repairs damage caused by DNA interstrand crosslinks. At least 8 of the 16 genes found mutated in FA encode proteins that assemble into the FA core complex, a multisubunit monoubiquitin E3 ligase. Here, we show that the RuvBL1 and RuvBL2 AAA+ ATPases co-purify with FA core complex isolated under stringent but native conditions from a vertebrate cell line. Depletion of the RuvBL1-RuvBL2 complex in human cells causes hallmark features of FA including DNA crosslinker sensitivity, chromosomal instability and defective FA pathway activation. Genetic knockout of RuvBL1 in a murine model is embryonic lethal while conditional inactivation in the haematopoietic stem cell pool confers profound aplastic anaemia. Together these findings reveal a function for RuvBL1-RuvBL2 in DNA repair through a physical and functional association with the FA core complex. Surprisingly, depletion of RuvBL1-RuvBL2 leads to co-depletion of the FA core complex in human cells. This suggests that a potential mechanism for the role of RuvBL1-RuvBL2 in maintaining genome integrity is through controlling the cellular abundance of FA core complex.

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Section: Resultsmentioning

confidence: 99%