Concerted cutting by Spo11 illuminates meiotic DNA break mechanics

In response to DNA damage, cells activate a phosphorylation-based signaling cascade known as the DNA damage response (DDR). One of the main outcomes of DDR activation is inhibition of cyclin-dependent kinase (Cdk) activity to restrain cell cycle progression until lesions are healed. Recent studies have revealed a reverse connection by which Cdk activity modulates processing of DNA break ends and DDR activation. However, the specific contribution of individual Cdks to this process remains poorly understood. To address this issue, we have examined the DDR in murine cells carrying a defined set of Cdks. Our results reveal that genome maintenance programs of postreplicative cells, including DDR, are regulated by the overall level of Cdk activity and not by specific Cdks.

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The Intra- and Extra-Telomeric Role of TRF2 in the DNA Damage Response

International Journal of Molecular Sciences ◽

10.3390/ijms22189900 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9900

Author(s):

Siti A. M. Imran ◽

Muhammad Dain Yazid ◽

Wei Cui ◽

Yogeswaran Lokanathan

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Response Factors ◽

Telomere Repeat ◽

Protection Mechanism ◽

Dna Instability ◽

Binding Factor ◽

Damage Response ◽

Dna Break

Telomere repeat binding factor 2 (TRF2) has a well-known function at the telomeres, which acts to protect the telomere end from being recognized as a DNA break or from unwanted recombination. This protection mechanism prevents DNA instability from mutation and subsequent severe diseases caused by the changes in DNA, such as cancer. Since TRF2 actively inhibits the DNA damage response factors from recognizing the telomere end as a DNA break, many more studies have also shown its interactions outside of the telomeres. However, very little has been discovered on the mechanisms involved in these interactions. This review aims to discuss the known function of TRF2 and its interaction with the DNA damage response (DDR) factors at both telomeric and non-telomeric regions. In this review, we will summarize recent progress and findings on the interactions between TRF2 and DDR factors at telomeres and outside of telomeres.

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HPF1 dynamically controls the PARP1/2 balance between initiating and elongating ADP-ribose modifications

Nature Communications ◽

10.1038/s41467-021-27043-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Marie-France Langelier ◽

Ramya Billur ◽

Aleksandr Sverzhinsky ◽

Ben E. Black ◽

John M. Pascal

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Chain Elongation ◽

Dna Breaks ◽

Data Support ◽

Damage Response ◽

Hit And Run ◽

Dna Break ◽

Structural Insights ◽

In Cells

AbstractPARP1 and PARP2 produce poly(ADP-ribose) in response to DNA breaks. HPF1 regulates PARP1/2 catalytic output, most notably permitting serine modification with ADP-ribose. However, PARP1 is substantially more abundant in cells than HPF1, challenging whether HPF1 can pervasively modulate PARP1. Here, we show biochemically that HPF1 efficiently regulates PARP1/2 catalytic output at sub-stoichiometric ratios matching their relative cellular abundances. HPF1 rapidly associates/dissociates from multiple PARP1 molecules, initiating serine modification before modification initiates on glutamate/aspartate, and accelerating initiation to be more comparable to elongation reactions forming poly(ADP-ribose). This “hit and run” mechanism ensures HPF1 contributions to PARP1/2 during initiation do not persist and interfere with PAR chain elongation. We provide structural insights into HPF1/PARP1 assembled on a DNA break, and assess HPF1 impact on PARP1 retention on DNA. Our data support the prevalence of serine-ADP-ribose modification in cells and the efficiency of serine-ADP-ribose modification required for an acute DNA damage response.

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