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Biological systems have a remarkable capability of synthesizing multifunctional materials that are adapted for specific physiological and ecological needs. When exploring structure–function relationships related to multifunctionality in nature, it can be a challenging task to address performance synergies, trade-offs, and the relative importance of different functions in biological materials, which, in turn, can hinder our ability to successfully develop their synthetic bioinspired counterparts. Here, we investigate such relationships between the mechanical and optical properties in a multifunctional biological material found in the highly protective yet conspicuously colored exoskeleton of the flower beetle, Torynorrhina flammea. Combining experimental, computational, and theoretical approaches, we demonstrate that a micropillar-reinforced photonic multilayer in the beetle’s exoskeleton simultaneously enhances mechanical robustness and optical appearance, giving rise to optical damage tolerance. Compared with plain multilayer structures, stiffer vertical micropillars increase stiffness and elastic recovery, restrain the formation of shear bands, and enhance delamination resistance. The micropillars also scatter the reflected light at larger polar angles, enhancing the first optical diffraction order, which makes the reflected color visible from a wider range of viewing angles. The synergistic effect of the improved angular reflectivity and damage localization capability contributes to the optical damage tolerance. Our systematic structural analysis of T. flammea’s different color polymorphs and parametric optical and mechanical modeling further suggest that the beetle’s microarchitecture is optimized toward maximizing the first-order optical diffraction rather than its mechanical stiffness. These findings shed light on material-level design strategies utilized in biological systems for achieving multifunctionality and could thus inform bioinspired material innovations.

DNA damage tolerance (DDT) enables bypassing of DNA lesions during replication, thereby preventing fork stalling, replication stress, and secondary DNA damage related to fork stalling. Three modes of DDT have been documented: translesion synthesis (TLS), template switching (TS), and repriming. TLS and TS depend on site-specific PCNA K164 monoubiquitination and polyubiquitination, respectively. To investigate the role of DDT in maintaining hematopoietic stem cells (HSCs) and progenitors, we used PcnaK164R/K164R mice as a unique DDT-defective mouse model. Analysis of the composition of HSCs and HSC-derived multipotent progenitors (MPPs) revealed a significantly reduced number of HSCs, likely owing to increased differentiation of HSCs toward myeloid/erythroid-associated MPP2s. This skewing came at the expense of the number of lymphoid-primed MPP4s, which appeared to be compensated for by increased MPP4 proliferation. Furthermore, defective DDT decreased the numbers of MPP-derived common lymphoid progenitor (CLP), common myeloid progenitor (CMP), megakaryocyte-erythroid progenitor (MEP), and granulocyte-macrophage progenitor (GMP) cells, accompanied by increased cell cycle arrest in CMPs. The HSC and MPP phenotypes are reminiscent of premature aging and stressed hematopoiesis, and indeed progressed with age and were exacerbated on cisplatin exposure. Bone marrow transplantations revealed a strong cell intrinsic defect of DDT-deficient HSCs in reconstituting lethally irradiated mice and a strong competitive disadvantage when cotransplanted with wild-type HSCs. These findings indicate a critical role of DDT in maintaining HSCs and progenitor cells, and in preventing premature aging.

DNA damage threatens genomic integrity and instigates stem cell failure. To bypass genotoxic lesions during replication, cells employ DNA damage tolerance (DDT), which is regulated via PCNA ubiquitination and REV1. DDT is conserved in all domains of life, yet its relevance in mammals remains unclear. Here, we show that inactivation of both PCNA-ubiquitination and REV1 results in embryonic and adult lethality, and the accumulation of DNA damage in hematopoietic stem and progenitor cells (HSPCs) that ultimately resulted in their depletion. Our results reveal the crucial relevance of DDT in the maintenance of stem cell compartments and mammalian life in unperturbed conditions.

Schlafen family member 11 (SLFN11) expression sensitizes cells to a spectrum of DNA-damaging chemotherapies. Previous studies have shown that SLFN11 is recruited to stalled replication forks in response to replication stress; however, the role of SLFN11 at stressed replication forks remains unclear. Using single-molecule DNA fiber analysis and super-resolution microscopy to interrogate the dynamics of individual replication forks, we show that SLFN11 acts upon stalled replication forks to suppress efficient fork restart. In the absence of SLFN11 expression, fork restart proceeds through a pathway involving the ubiquitin ligase RFWD3 and the DNA primase-polymerase PRIMPOL to facilitate gapped DNA synthesis, thereby ensuring that cells do not accumulate replication-associated DNA damage. SLFN11 antagonizes this pathway by disrupting recruitment of RFWD3 and PRIMPOL to stalled forks in a manner dependent on a functional ATPase domain and persistent fork localization, but not on tRNA hydrolysis or ssDNA binding. Collectively, our results provide a mechanistic basis for how SLFN11 can counteract DNA damage tolerance by suppressing the RFWD3-PRIMPOL fork restart pathway. SLFN11 is a predictive marker of chemosensitivity that results in elevated replication stress, but how it regulates replication fork dynamics remains unclear. Here, the authors use super-resolution microscopy to determine how SLFN11 inhibits the function of RFWD3- PRIMPOL to suppress fork restart.

ABSTRACT What is the origin of mutations? In contrast to the naïve notion that mutations are unfortunate accidents, genetic research in microorganisms has demonstrated that most mutations are created by genetically encoded error-prone repair mechanisms. However, error-free repair pathways also exist, and it is still unclear how cells decide when to use one repair method or the other. Here, we summarize what is known about the DNA damage tolerance mechanisms (also known as post-replication repair) for perhaps the best-studied organism, the yeast Saccharomyces cerevisiae. We describe the latest research, which has established the existence of at least two error-free and two error-prone inter-related mechanisms of damage tolerance that compete for the handling of spontaneous DNA damage. We explore what is known about the induction of mutations by DNA damage. We point to potential paradoxes and to open questions that still remain unanswered. We summarize current knowledge on the mechanisms that create mutations in yeast.

A major quality challenge in the application of titanium alloys is the persistence of substances known as “hard-alpha inclusions”. Although hard-alpha inclusions are extremely rare and typically small in size in high-quality titanium alloys for aero-engine disks, their hard and brittle nature poses a non-negligible threat to the structural integrity of the disks. Due to the extreme scarcity of natural hard-alpha inclusions, most previous studies have focused on “synthetic dense hard-alpha particles” rather than “real porous hard-alpha inclusions”, inevitably over-looking the differences between them. In this work, a method of introducing titanium nitride sponge preforms into the electrode preparation step of the smelting process is proposed and implemented, successfully fabricating real porous hard-alpha inclusions in TC4 titanium alloy disks. On this basis, the detection characteristics of ultrasonic non-destructive testing for such porous hard-alpha inclusions are investigated, and a probability of detection (POD) model for these defects is established for the first time. A defect distribution model of porous hard-alpha inclusions for the probabilistic damage tolerance assessment of disks is also derived. This work reveals that, unlike the “linear” behavior of traditional models, the new defect distribution model adheres to a “cubic polynomial” relationship.

Traditional evaluation of accumulative damage calculates fatigue life of metro’s bogie frame based on material properties and stress spectrums, which has limitation on evaluating accurate life due to non-crack assumption. In this paper, crack propagation is numerically simulated to give more accurate result, showing that a crack’s initial geometry has great effects on reducing fatigue life cycles, and the count of cycles required for a crack with an initial size of 3 mm and 5 mm to propagate to an equivalent crack length is 68.5 % and 48.3 %, respectively, in comparison to a 2 mm initial crack size. On this basis, damage tolerance analysis is introduced for optimizing anti-fatigue evaluation strategy and maintenance periods. The results suggest that accumulative damage and damage tolerance methods should be comprehensively combined for staging evaluation of bogie frame’s fatigue life, by establishing a control boundary between the initial crack and the critical crack, proactive repairs can be executed, which facilitates the ongoing usability of the bogie frame, leading to an extension of its effective operational periods.

DNA repair is essential to maintain genome integrity. In addition to various DNA repair pathways dealing with specific types of DNA lesions, DNA damage tolerance (DDT) promotes the bypass of DNA replication blocks encountered by the replication fork to prevent cell death. Budding yeast Rad5 plays an essential role in the DDT pathway and its structure indicates that Rad5 recognizes damaged DNA or stalled replication forks, suggesting that Rad5 plays an important role in the DDT pathway choice. It has been reported that Rad5 forms subnuclear foci in the presence of methyl methanesulfonate (MMS) during the S phase. By analyzing the formation of Rad5 foci after MMS treatment, we showed that some specific DNA structures rather than mono-ubiquitination of proliferating cell nuclear antigen are required for the recruitment of Rad5 to the damaged site. Moreover, inactivation of the base excision repair (BER) pathway greatly decreased the Rad5 focus formation, suggesting that Rad5 recognizes specific DNA structures generated by BER. We also identified a negative role of overexpressed translesion synthesis polymerase Polη in the formation of Rad5 foci. Based on these data, we propose a modified DDT pathway model in which Rad5 plays a role in activating the DDT pathway.

Cells expend a large amount of energy to maintain their DNA sequence. DNA repair pathways, cell cycle checkpoint activation, proofreading polymerases, and chromatin structure are ways in which the cell minimizes changes to the genome. During replication, the DNA-damage tolerance pathway allows the replication forks to bypass damage on the template strand. This avoids prolonged replication fork stalling, which can contribute to genome instability. The DNA-damage tolerance pathway includes two subpathways: translesion synthesis and template switch. Post-translational modification of PCNA and the histone tails, cell cycle phase, and local DNA structure have all been shown to influence subpathway choice. Chromatin architecture contributes to maintaining genome stability by providing physical protection of the DNA and by regulating DNA-processing pathways. As such, chromatin-binding factors have been implicated in maintaining genome stability. Using Saccharomyces cerevisiae, we examined the role of Spn1 (Suppresses postrecruitment gene number 1), a chromatin-binding and transcription elongation factor, in DNA-damage tolerance. Expression of a mutant allele of SPN1 results in increased resistance to the DNA-damaging agent methyl methanesulfonate, lower spontaneous and damage-induced mutation rates, along with increased chronological life span. We attribute these effects to an increased usage of the template switch branch of the DNA-damage tolerance pathway in the spn1 strain. This provides evidence for a role of wild-type Spn1 in promoting genome instability, as well as having ties to overcoming replication stress and contributing to chronological aging.

Establishing probability of detection (POD) or reliability of various nondestructive testing (NDT) techniques is essential for implementing damage tolerant (DT) methodology for aero-engines. This POD is usually established with the help of a large number of service expired aero-engine components containing several fatigue cracks. In the absence of such components, artificial defects such as electrical discharge machining (EDM) notches or starter cracks were explored. However, such artificial defects would not meet the key features such as tightness of the fatigue cracks and the possible oxidation in the crack opening and thus, limiting their usage. Therefore, in the current study, an innovative approach of generating fatigue cracks at 650 °C (~ typical aero-engine service temperatures) with key high temperature service degradation aspects of oxidation and fatigue cracking is demonstrated for the first time using Gleeble ® test system. Further, POD is estimated by inspecting these laboratory generated fatigue cracks using fluorescent liquid penetrant technique (FLPT) and eddy current technique (ECT) under HIT (defect detected) vs. MISS (defect not detected) and â (signal response) vs. a (crack size) methodologies. The current study also discusses a statistical approach of random generation of crack sizes for use in NDT reliability analysis. In addition, an attempt has been made to understand the effect of a 90/95 values on remnant life calculations. It is concluded that the eddy current response of oxidized fatigue cracks results in better (high sensitive) a 90/95 values compared to the eddy current response obtained from non-oxidized fatigue cracks.