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Mechanistic Insight Into Replication Fork Reversal Under Genotoxic Stress


Vujanovic, Marko. Mechanistic Insight Into Replication Fork Reversal Under Genotoxic Stress. 2016, University of Zurich, Faculty of Science.

Abstract

Replication fork reversal - the transaction from a three-way junction (the usual conformation of replication forks) to a four-way junction - has been reported as a general response in face of a wide variety of genotoxic agents, oncogene activation and difficult-to-replicate regions of the genome. Proteins mediating this molecular transaction in vivo are still elusive. Many different groups of proteins have been proposed to execute this operation, yet most of the data come from biochemical experiments that may hardly recapitulate the complexity of this transaction in vivo. We focused our research on two groups of proteins, such as annealing helicases and post replicative repair (PRR) factors. The first group of proteins (SMARCAL1 and ZRANB3) have the unique ability to re-anneal RPA coated single stranded DNA (ssDNA), which may be necessary to convert standard replication forks to reversed forks. The second group of proteins (e.g. the E2 ubiquitin-conjugating enzyme UBC13 and polyubiquitinated PCNA) was selected as previous studies suggested the error-free branch of PRR to operate via template switching mechanisms, possibly entailing replication fork reversal. We could indeed determine that ZRANB3 is required for efficient fork slowing and reversal upon genotoxic stress and we are currently uncovering which domains are crucial for this function. We also uncovered the contribution of UBC13 and PCNA ubiquitination to active fork slowing and replication fork reversal upon genotoxic stress.

Abstract

Replication fork reversal - the transaction from a three-way junction (the usual conformation of replication forks) to a four-way junction - has been reported as a general response in face of a wide variety of genotoxic agents, oncogene activation and difficult-to-replicate regions of the genome. Proteins mediating this molecular transaction in vivo are still elusive. Many different groups of proteins have been proposed to execute this operation, yet most of the data come from biochemical experiments that may hardly recapitulate the complexity of this transaction in vivo. We focused our research on two groups of proteins, such as annealing helicases and post replicative repair (PRR) factors. The first group of proteins (SMARCAL1 and ZRANB3) have the unique ability to re-anneal RPA coated single stranded DNA (ssDNA), which may be necessary to convert standard replication forks to reversed forks. The second group of proteins (e.g. the E2 ubiquitin-conjugating enzyme UBC13 and polyubiquitinated PCNA) was selected as previous studies suggested the error-free branch of PRR to operate via template switching mechanisms, possibly entailing replication fork reversal. We could indeed determine that ZRANB3 is required for efficient fork slowing and reversal upon genotoxic stress and we are currently uncovering which domains are crucial for this function. We also uncovered the contribution of UBC13 and PCNA ubiquitination to active fork slowing and replication fork reversal upon genotoxic stress.

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Additional indexing

Item Type:Dissertation
Referees:Lopes Massimo, Boulton Simon J, Cejka Petr, Pichierri Pietro
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2016
Deposited On:20 Dec 2016 13:19
Last Modified:28 Apr 2017 05:52

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