Abstract
Components of the nuclear pore complex (NPC) have been shown to play a crucial role in protecting against replication stress, and recovery from some types of stalled or collapsed replication forks requires movement of the DNA to the NPC in order to maintain genome stability. The role that nuclear positioning has on DNA repair has been investigated in several systems that inhibit normal replication. These include structure forming sequences (expanded CAG repeats), protein mediated stalls (replication fork barriers (RFBs)), stalls within the telomere sequence, and the use of drugs known to stall or collapse replication forks (HU + MMS or aphidicolin). Recently, the mechanism of relocation for collapsed replication forks to the NPC has been elucidated. Here, we will review the types of replication stress that relocate to the NPC, the current models for the mechanism of relocation, and the currently known protective effects of this movement.
Highlights
DNA must be accurately and efficiently replicated once during each cell cycle in order to maintain the genome
Even if replication cannot be restarted, the nascent DNA can be protected by the replisome remaining bound to the DNA until other restart pathways can be initiated. Examples of these alternative restart pathways are convergence with an oncoming fork from an active origin [5,6,7], re-priming downstream of damaged DNA bases followed by filling in of the ssDNA gaps left behind [8,9], and a homologous recombination-dependent fork restart known as recombination-dependent replication (RDR) [10]
Sumoylation of target proteins is mediated by Ubc9, the SUMO E2 conjugating enzyme, and three SUMO E3 ligases in budding yeast: Mms21/Nse2, Siz1, and Siz2
Summary
DNA must be accurately and efficiently replicated once during each cell cycle in order to maintain the genome. An example of a structure that could form is a reversed fork These are commonly formed in response to replication stress, especially in areas of the genome that are difficult to replicate or have DNA damage [11]. Cells could attempt to repair or restart the collapsed fork through homologous recombination (HR)-mediated mechanisms such as RDR This can result in increased genome instability, it is generally better than leaving DNA unreplicated [10,17]. In mammalian cells, replication forks were shown to interact with nuclear pore complex components when under replication stress (personal communication, Dr Anja Bielinsky). It seems that, in cases where cells are dealing with replication stress, it is important to have components of the nuclear pore Y-complex, pointing to the complex playing a role in dealing with the replication stress
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