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“The role of ALC1, a novel ATP-dependent chromatin remodelling protein, in transcriptional regulation, tumorigenesis and neurodegeneration”


The genome is continuously exposed to DNA damaging insults that induce a wide variety of lesions. For a proper DNA damage signalling and repair, chromatin remodelling is most likely a prerequisite. Poly(ADP-ribose) (PAR) is known to induce chromatin relaxation at DNA damage sites but how this is achieved remains unclear. My host lab recently identified ALC1 (Amplified in Liver Cancer 1) that binds to PAR via a C-terminal Macro domain and catalyzes PARP1-stimulated nucleosome sliding by an N-terminal helicase core (Ahel, et al., 2009). A role for ALC1 in DNA repair is supported by its rapid PAR-dependent recruitment to DNA breaks and by the sensitivity of ALC1-depleted cells to DNA damage agents. This study revealed that ALC1 promotes PAR-dependent chromatin relaxation at DNA damage sites (Ahel, et al., 2009). These findings also have important clinical implications as hALC1 was identified as the target oncogene within the 1q21 amplicon, a frequent genetic alteration in human hepatocellular carcinoma (Ma et al., 2008). Here, I propose to study the potential role of ALC1 in chromatin remodelling at PARP1 regulated promoters. In parallel, I propose to generate gain-of function and loss-of function ALC1 mouse mutants. On the one hand, I will generate mALC1 inducible transgenic mice to establish its potential role in tumorigenesis. On the other hand, I will generate mALC1 conditional knock-out mice to study its role in neurodegenerative diseases as already described for some SSB repair-response proteins. Bibliography Ahel D , Hořejší Z, Wiechens N, Polo SE, Garcia-Wilson E, Ahel I, Flynn H, Skehel M, West SC, Jackson SP, Owen-Hughes T and Boulton, SJ. Science. 2009. Ma NF, Hu L, Fung JM, Xie D, Zheng BJ, Chen L, Tang DJ, Fu L, Wu Z, Chen M, Fang Y, Guan XY. Hepatology. 2008.

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London Inner London — West Camden and City of London
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Holly Elphinstone (Ms.)
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