Presence control of DNA repair controllers

This article refers to:

A role for homologous recombination proteins in cell cycle regulation

Proteins involved in DNA repair not only repair DNA damages but also participate in DNA damage signaling, thus enabling the cells to stops the progression of their cell cycle until the repair is done. If cells were allowed to progress through the cell cycle with unrepaired DNA this would lead to genome instability, which can cause cancer in higher eukaryotes. DNA repair and signaling of DNA damage is an intricate process where different proteins control each other¹ and where repair proteins in addition to their direct role in DNA repair serve also as sensors of the damage and thus also as controllers that the repair has ben done correctly.² If the quality controllers of DNA repair were absent, as would be the case when some of DNA damage response genes acquired a mutation, the affected cells would in a way “not know” whether their DNA passed successfully the quality check or not. Can cells detect in such cases the absence of important DNA repair proteins and stop the progression of their cell cycle, thus protecting multicellular organism from cancer?

In this issue of Cell Cycle Kostyrko et al.³ addressed this question by systematically knocking down genes coding for a dozen of important proteins participating in DNA damage response and repair pathways (BRCA1, CtIP, MDC1, MRE11, NBS1 RAD51, RAD51B, RAD51C, RAD51D, RAD52, RAD54, XRCC2). Importantly, the effects of these knock downs were assayed in cultured Chinese hamster ovary (CHO) cells that were not exposed to any non-physiological DNA damages. To follow the cell cycle progression of cells depleted of individual DNA repair proteins, the authors have used fluorescent ubiquitination-based cell cycle indicator system (Fucci).⁴ The authors observed that, depending on the missing DNA repair protein, the cells stopped the progression of their cell cycle either at G2 phase, as it was the case when RAD51 protein was missing, or at G1/G0 stage when RAD50 was depleted. Although Kostyrko et al.³ did not try to characterize the underlying molecular mechanisms that are responsible for the observed cell cycle arrest, their results suggest that cells may possess mechanisms that give the stop signal when some of DNA repair proteins are missing, and that this happens even when there is no significant DNA damage.

Let us consider here possible mechanisms that could arrest cells that are not exposed to DNA damage treatments when some of DNA repair proteins, such as RAD51, are missing. It is known that RAD51^−/− mutations are not only embryonic lethal but also lethal on the level of knocked out cells.⁵ Is this lethality due to the lack of some essential functions in normally growing cells, or rather to the signaling of the mere absence of Rad51? DNA damages, such as replication fork collapse, may be sufficiently frequent in normally growing cells so that they would be unable to finish their replication without RAD51-mediated repair.⁶ However, in the absence of the quality controllers of DNA repair, the cells may not notice that the repair of collapsed replication forks was not correctly done and thus may progress with their cell cycle. Can there be a mechanism that could stop the progression of cell cycle without DNA damage, when essential DNA repair proteins are missing? Existence of such a mechanism was suggested by the observation that several homologous recombination proteins associate with centrosomes and that this association is required for centrosomes' action.⁷ Capelli et al.⁷ proposed that several DNA repair proteins may show higher affinity to damaged DNA than to the centrosomes. However, once the repair is completed, these DNA repair proteins will be free to associate with centrosomes making them functional. Such a mechanism would stop the progression of the cell cycle when RAD51 or other homologous recombination proteins needed for centromeres' action were busy repairing the DNA or were simply missing. This mechanism would operate also in the absence of any DNA damage. Thus, the proposed cellular strategy to control for the presence of important repair proteins resembles the one used in banks. Some important safes need to be opened simultaneously using several different keys assigned to several different persons, thus assuring that all authorized persons are there when the safe is being opened.