Control of the chromatin response to DNA damage: Histone proteins pull the strings.

DNA damage challenges both genome integrity and its organization with histone proteins into chromatin, with prominent alterations in histone variant dynamics and histone modifications. While these alterations jeopardize epigenome stability, they are also instrumental for an efficient and timely response to DNA damage. Here, we review recent findings illustrating how histone variants and post-translational modifications actively contribute to and control the DNA damage response. We present accumulating evidence that histone protein changes help relieve the chromatin barrier to DNA repair by regulating chromatin compaction and mobility. We also highlight how histone modifications and variants control transcriptional silencing at damage sites, and we describe both pre-existing and DNA damage-induced chromatin features that govern DNA damage signaling and guide DNA repair pathway choice. We discuss how histone dynamics ultimately participate to the restoration of epigenome integrity and present our current knowledge of key molecular players involved in these critical processes.

On this side of the fence: Functional responses to linear landscape features shape the home range of large herbivores.

Understanding the consequences of global change for animal movement is a major issue for conservation and management. In particular, habitat fragmentation generates increased densities of linear landscape features that can impede movements. While the influence of these features on animal movements has been intensively investigated, they may also play a key role at broader spatial scales (e.g. the home range scale) as resources, cover from predators/humans, corridors/barriers or landmarks. How space use respond to varying densities of linear features has been mostly overlooked in large herbivores, in contrast to studies done on predators. Focusing on large herbivores should provide additional insights to understand how animals solve the trade-off between energy acquisition and mortality risk. Here, we investigated the role of anthropogenic (roads and tracks) and natural (ridges, valley bottoms and forest edges) linear features on home range features in five large herbivores. We analysed an extensive GPS monitoring database of 710 individuals across nine populations, ranging from mountain areas mostly divided by natural features to lowlands that were highly fragmented by anthropogenic features. Nearly all of the linear features studied were found at the home range periphery, suggesting that large herbivores primarily use them as landmarks to delimit their home range. In contrast, for mountain species, ridges often occurred in the core range, probably related to their functional role in terms of resources and refuge. When the density of linear features was high, they no longer occurred predominantly at the home range periphery, but instead were found across much of the home range. We suggest that, in highly fragmented landscapes, large herbivores are constrained by the costs of memorising the spatial location of key features, and by the requirement for a minimum area to satisfy their vital needs. These patterns were mostly consistent in both males and females and across species, suggesting that linear features have a preponderant influence on how large herbivores perceive and use the landscape.

Mitotic chromatin marking governs asymmetric segregation of DNA damage.

The faithful segregation of intact genetic material and the perpetuation of chromatin states through mitotic cell divisions are pivotal for maintaining cell function and identity across cell generations. However, most exogenous mutagens generate long-lasting DNA lesions that are segregated during mitosis. How this segregation is controlled is unknown. Here, we uncover a mitotic chromatin-marking pathway that governs the segregation of UV-induced damage in human cells. Our mechanistic analyses reveal two layers of control: histone ADP-ribosylation, and the incorporation of newly synthesized histones at UV damage sites, that both prevent local mitotic phosphorylations on histone H3 serines. Functionally, this chromatin-marking pathway drives the asymmetric segregation of UV damage in the cell progeny with potential consequences on daughter cell fate. We propose that this mechanism may help preserve the integrity of stem cell compartments during asymmetric cell divisions.

Dissecting regulatory pathways for transcription recovery following DNA damage reveals a non-canonical function of the histone chaperone HIRA.

Transcription restart after a genotoxic challenge is a fundamental yet poorly understood process. Here, we dissect the interplay between transcription and chromatin restoration after DNA damage by focusing on the human histone chaperone complex HIRA, which is required for transcription recovery post UV. We demonstrate that HIRA is recruited to UV-damaged chromatin via the ubiquitin-dependent segregase VCP to deposit new H3.3 histones. However, this local activity of HIRA is dispensable for transcription recovery. Instead, we reveal a genome-wide function of HIRA in transcription restart that is independent of new H3.3 and not restricted to UV-damaged loci. HIRA coordinates with ASF1B to control transcription restart by two independent pathways: by stabilising the associated subunit UBN2 and by reducing the expression of the transcription repressor ATF3. Thus, HIRA primes UV-damaged chromatin for transcription restart at least in part by relieving transcription inhibition rather than by depositing new H3.3 as an activating bookmark.

Water-level fluctuation enhances sediment and trace metal mobility in lake littoral.

Water-level fluctuation (WLF) is a widespread management action in lakes and reservoirs whose impacts on contaminant fate have seldom been investigated. We used near shore hourly measurements (n = 2122) of turbidity (contaminant proxy) and water velocity (sediment resuspension proxy) to track high-frequency contaminant dynamics during a 0.6 m change in water level observed in autumn 2017 in a large French lake. Simultaneously, discrete trace metal measurements highlighted that trapped sediment was more contaminated and finer than surficial sediment supporting that suspended particles (measured by turbidity) were a preferential medium for contaminant mobility. General additive models involving tensor products revealed the enhancement of wind-speed and river discharge effects on turbidity with water draw down. The decrease of the explained deviances by the models over time-lags indicated short time-scale response of turbidity to external forcing. Three of the four major turbid events occurred at the lowest water-level and were concomitant of sediment resuspension as well as precipitation events and/or river flood suggesting a complex interplay among in-lake and watershed processes at controlling sediment mobility during the WLF. These results shed in light that WLF can affect lake littoral hydrodynamic cascading up to the enhancement of contaminant mobility. Sediment resuspension may be an overlooked feature of WLF increasing contamination risk and exposure for littoral organisms with widespread ecological consequences due to the large number of water-level regulated ecosystems.

Histone Variants: Guardians of Genome Integrity.

Chromatin integrity is key for cell homeostasis and for preventing pathological development. Alterations in core chromatin components, histone proteins, recently came into the spotlight through the discovery of their driving role in cancer. Building on these findings, in this review, we discuss how histone variants and their associated chaperones safeguard genome stability and protect against tumorigenesis. Accumulating evidence supports the contribution of histone variants and their chaperones to the maintenance of chromosomal integrity and to various steps of the DNA damage response, including damaged chromatin dynamics, DNA damage repair, and damage-dependent transcription regulation. We present our current knowledge on these topics and review recent advances in deciphering how alterations in histone variant sequence, expression, and deposition into chromatin fuel oncogenic transformation by impacting cell proliferation and cell fate transitions. We also highlight open questions and upcoming challenges in this rapidly growing field.