Double-strand breaks (DSBs) are extremely cytotoxic DNA lesions. If not properly repaired, they cause pathological alterations either in the structure or in the sequence of chromosomes, significantly increasing genome instability and predisposition to cancer development in higher eukaryotes. As a consequence, cells evolved an elaborate network of mechanisms that rapidly recognize and repair strand breaks, protecting genome integrity. This process, globally known as DNA Damage Response (DDR), consists mainly in the activation of both the DNA damage checkpoint and specific repair pathways (i.e. Non Homologous End Joining (NHEJ) and Homologous Recombination (HR), in the case of DSBs), coupled with chromatin remodeling and modulation of gene expression. In the last few years, many studies uncovered the essential contribution of ubiquitination and SUMOylation in the control of the DDR. I report a new role for the two budding yeast FHA-RING ubiquitin ligases Dma1 and Dma2 in regulating the response to DSB. In particular, I show that these proteins are required for the repair of specific DNA lesions characterized by dirty ends, such as those generated by bleocin. According to my data, Dma1 and Dma2 are recruited to damaged chromatin and, through ubiquitination, promote the removal from DNA of the MRX complex, which is otherwise persistently blocked at Bleocin-induced modified ends. Stable accumulation of the MRX complex at the break site causes severe defects in the repair of broken chromosomes and a strong Tel1-dependent DNA damage checkpoint hyperactivation. In conclusion, I propose that Dma1 and Dma2 play a critical role in the resolution of DNA-protein crosslink at DSB ends, probably through the direct ubiquitination and degradation via proteasome of the crosslinked factor.

DMA1 AND DMA2: NOVEL REGULATORS OF DOUBLE-STRAND BREAK RESPONSE IN S. CEREVISIAE / M. Bertolotti ; tutor: F. Lazzaro ; coordinatore: M. Muzi-Falconi. - : . Università degli Studi di Milano, 2019 May 07. ((31. ciclo, Anno Accademico 2018. [10.13130/bertolotti-marta_phd2019-05-07].

DMA1 AND DMA2: NOVEL REGULATORS OF DOUBLE-STRAND BREAK RESPONSE IN S. CEREVISIAE

M. Bertolotti
2019-05-07

Abstract

Double-strand breaks (DSBs) are extremely cytotoxic DNA lesions. If not properly repaired, they cause pathological alterations either in the structure or in the sequence of chromosomes, significantly increasing genome instability and predisposition to cancer development in higher eukaryotes. As a consequence, cells evolved an elaborate network of mechanisms that rapidly recognize and repair strand breaks, protecting genome integrity. This process, globally known as DNA Damage Response (DDR), consists mainly in the activation of both the DNA damage checkpoint and specific repair pathways (i.e. Non Homologous End Joining (NHEJ) and Homologous Recombination (HR), in the case of DSBs), coupled with chromatin remodeling and modulation of gene expression. In the last few years, many studies uncovered the essential contribution of ubiquitination and SUMOylation in the control of the DDR. I report a new role for the two budding yeast FHA-RING ubiquitin ligases Dma1 and Dma2 in regulating the response to DSB. In particular, I show that these proteins are required for the repair of specific DNA lesions characterized by dirty ends, such as those generated by bleocin. According to my data, Dma1 and Dma2 are recruited to damaged chromatin and, through ubiquitination, promote the removal from DNA of the MRX complex, which is otherwise persistently blocked at Bleocin-induced modified ends. Stable accumulation of the MRX complex at the break site causes severe defects in the repair of broken chromosomes and a strong Tel1-dependent DNA damage checkpoint hyperactivation. In conclusion, I propose that Dma1 and Dma2 play a critical role in the resolution of DNA-protein crosslink at DSB ends, probably through the direct ubiquitination and degradation via proteasome of the crosslinked factor.
LAZZARO, FEDERICO
Settore BIO/11 - Biologia Molecolare
DMA1 AND DMA2: NOVEL REGULATORS OF DOUBLE-STRAND BREAK RESPONSE IN S. CEREVISIAE / M. Bertolotti ; tutor: F. Lazzaro ; coordinatore: M. Muzi-Falconi. - : . Università degli Studi di Milano, 2019 May 07. ((31. ciclo, Anno Accademico 2018. [10.13130/bertolotti-marta_phd2019-05-07].
Doctoral Thesis
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/634772
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