Anita Göndör Group
DNA repair and chromosome crosstalk: a two-way relationship
The spatial distribution of the genetic material in the nucleus is not random. Factors, known to be involved in the reparation of damaged DNA turned out to play unanticipated roles in arranging the genome in 3D to influence gene expression.
The DNA damage response (DDR) pathways constitute pivotal features of the cell that are invariably associated to diseases when malfunctioning. Recently, it has been pointed out that members of the DDR machinery, such as poly(ADP-ribose) polymerase 1 (PARP1) and ATM, have non-canonical functions beyond DNA repair, and regulate developmental processes via participating in transcriptional regulation and signal transduction (1).
We have discovered a novel function of PARP1 and find that it regulates chromatin mobility and transient encounters between chromatin fibres in interphase nuclei. These dynamic physical interactions between chromosomes establish non-random, epigenetically regulated, modular chromosomal networks (fig. 1.) and provide platforms for the fine-tuning and coordination of nuclear functions (2-3). The generation of PAR at central chromatin hubs depends on a feed back loop between PARP1 and CTCF- a “master weaver” of chromatin loops (2). Thus, CTCF binds to PARP1 and activates its enzymatic activity in vitro and potentially also in vivo. Most interestingly, the CTCF-PARP1 interaction is lost upon TGF-beta-induced epithelial to mesenchymal transition, concomitant with the disassembly of the PAR-dependent chromatin fibre interactome. Since regulators of epithelial cell polarity are among the interacting sequences, the reorganization of chromatin fibre interactome might represent a so far unrecognized feature necessary for the phenotypic transition during EMT.
Building on these observations, we plan to examine further the mechanisms how members of the DNA repair machinery are recruited to central chromatin hubs to modulate the transcriptome upon signals of the microenvironment. Moreover, these perspectives reveal a potential interface between DNA damage, cell cycle checkpoints and higher order chromatin structure.
Epigenetic modulators, modifiers and mediators in cancer aetiology and progression.
Nat. Rev. Genet. 2016 May;17(5):284-99
PARP1- and CTCF-Mediated Interactions between Active and Repressed Chromatin at the Lamina Promote Oscillating Transcription.
Mol. Cell 2015 Sep;59(6):984-97
Chromatin in situ proximity (ChrISP): single-cell analysis of chromatin proximities at a high resolution.
BioTechniques 2014 ;56(3):117-8, 120-4
Nuclear architecture and chromatin structure on the path to cancer.
Semin. Cancer Biol. 2013 Apr;23(2):63-4
Dynamic chromatin loops bridge health and disease in the nuclear landscape.
Semin. Cancer Biol. 2013 Apr;23(2):90-8
Window into the complexities of chromosome interactomes.
Cold Spring Harb. Symp. Quant. Biol. 2010 ;75():493-500
Chromosome crosstalk in three dimensions.
Nature 2009 Sep;461(7261):212-7
High-resolution circular chromosome conformation capture assay.
Nat Protoc 2008 ;3(2):303-13