PAXX promotes KU accumulation at DNA breaks and is essential for end-joining in XLF-deficient mice

Non-homologous end-joining (NHEJ) is the most prominent DNA double strand break (DSB) repair pathway in mammalian cells. PAXX is the newest NHEJ factor, which shares structural similarity with known NHEJ factors—XRCC4 and XLF. Here we report that PAXX is dispensable for physiological NHEJ in otherwise wild-type mice. Yet Paxx−/− mice require XLF and Xlf−/− mice require PAXX for end-ligation. As such, Xlf−/−Paxx−/− mice display severe genomic instability and neuronal apoptosis, which eventually lead to embryonic lethality. Despite their structural similarities, only Xlf−/− cells, but not Paxx−/− cells require ATM/DNA-PK kinase activity for end-ligation. Mechanistically, PAXX promotes the accumulation of KU at DSBs, while XLF enhances LIG4 recruitment without affecting KU dynamics at DNA breaks in vivo. Together these findings identify the molecular functions of PAXX in KU accumulation at DNA ends and reveal distinct, yet critically complementary functions of PAXX and XLF during NHEJ

Alisol C 23-acetate from the rhizome of Alisma orientale

The title compound [systematic name: 11β-hydr­oxy-24,25-ep­oxy-3,16-oxo-protost-13 (17)-en-23-yl acetate], C32H48O6, a protostane-type triterpenoid, was isolated from the Chinese herbal medicine alismatis rhizoma (the rhizome of Alisma orientalis Juzep). The mol­ecule contains four trans-fused rings, viz. three six-membered and one five-membered ring. Two of the six-membered rings have slightly distorted half-chair conformations, while the third exhibits a chair conformation. The five-membered ring is almost planar. An inter­molecular O—H⋯O hydrogen bond between the hydr­oxy and ep­oxy groups and intra- and intermolecular C—H⋯O hydrogen bonds are observed

Functional redundancy between the XLF and DNA-PKcs DNA repair factors in V(D)J recombination and nonhomologous DNA end joining

Classical nonhomologous end joining (C-NHEJ) is a major mammalian DNA double-strand break (DSB) repair pathway that is required for assembly of antigen receptor variable region gene segments by V(D)J recombination. Recombination activating gene endonuclease initiates V(D)J recombination by generating DSBs between two V(D)J coding gene segments and flanking recombination signal sequences (RS), with the two coding ends and two RS ends joined by C-NHEJ to form coding joins and signal joins, respectively. During C-NHEJ, recombination activating gene factor generates two coding ends as covalently sealed hairpins and RS ends as blunt 5′-phosphorylated DSBs. Opening and processing of coding end hairpins before joining by C-NHEJ requires the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). However, C-NHEJ of RS ends, which do not require processing, occurs relatively normally in the absence of DNA-PKcs. The XRCC4-like factor (XLF) is a C-NHEJ component that is not required for C-NHEJ of chromosomal signal joins or coding joins because of functional redundancy with ataxia telangiectasia mutated kinase, a protein that also has some functional overlap with DNA-PKcs in this process. Here, we show that XLF has dramatic functional redundancy with DNA-PKcs in the V(D)J SJ joining process, which is nearly abrogated in their combined absence. Moreover, we show that XLF functionally overlaps with DNA-PKcs in normal mouse development, promotion of genomic stability in mouse fibroblasts, and in IgH class switch recombination in mature B cells. Our findings suggest that DNA-PKcs has fundamental roles in C-NHEJ processes beyond end processing that have been masked by functional overlaps with XLF

A comprehensive city-level final energy consumption dataset including renewable energy for China, 2005–2021

The role of China is increasingly pivotal in climate change mitigation, and the formulation of energy conservation and emission reduction policies requires city-level information. The effectiveness of national policy implementation is contingent upon the support and involvement of local governments. Accurate data on final energy consumption is vital to formulate and implement city-level energy transitions and energy conservation and emission reduction policies. However, there is a dearth of data sources pertaining to China’s city-level final energy consumption. To address these gaps, we developed computational modeling techniques along with top-down and downscaling methods to estimate China’s city-level final energy consumption. In this way, we compiled a final energy consumption inventory for 331 Chinese cities from 2005 to 2021, covering seven economic sectors, 30 fossil fuels, and four clean power sources. Moreover, we discussed the validity of the estimation results from multiple perspectives to enhance estimation accuracy. This dataset can be utilized for analysis in various cutting-edge research fields such as energy transition dynamics, transition risk management strategies, and policy formulation processes

A comprehensive city-level final energy consumption dataset including renewable energy for China, 2005–2021

The role of China is increasingly pivotal in climate change mitigation, and the formulation of energy conservation and emission reduction policies requires city-level information. The effectiveness of national policy implementation is contingent upon the support and involvement of local governments. Accurate data on final energy consumption is vital to formulate and implement city-level energy transitions and energy conservation and emission reduction policies. However, there is a dearth of data sources pertaining to China’s city-level final energy consumption. To address these gaps, we developed computational modeling techniques along with top-down and downscaling methods to estimate China’s city-level final energy consumption. In this way, we compiled a final energy consumption inventory for 331 Chinese cities from 2005 to 2021, covering seven economic sectors, 30 fossil fuels, and four clean power sources. Moreover, we discussed the validity of the estimation results from multiple perspectives to enhance estimation accuracy. This dataset can be utilized for analysis in various cutting-edge research fields such as energy transition dynamics, transition risk management strategies, and policy formulation processes

PARP inhibitors trap PARP2 and alter the mode of recruitment of PARP2 at DNA damage sites

Dual-inhibitors of PARP1 and PARP2 are promising anti-cancer drugs. In addition to blocking PARP1&amp;2 enzymatic activity, PARP inhibitors also extend the lifetime of DNA damage-induced PARP1&amp;2 foci, termed trapping. Trapping is important for the therapeutic effects of PARP inhibitors. Using live-cell imaging, we found that PARP inhibitors cause persistent PARP2 foci by switching the mode of PARP2 recruitment from a predominantly PARP1- and PAR-dependent rapid exchange to a WGR domain-mediated stalling of PARP2 on DNA. Specifically, PARP1-deletion markedly reduces but does not abolish PARP2 foci. The residual PARP2 foci in PARP1-deficient cells are DNA-dependent and abrogated by the R140A mutation in the WGR domain. Yet, PARP2-R140A forms normal foci in PARP1-proficient cells. In PARP1-deficient cells, PARP inhibitors - niraparib, talazoparib, and, to a lesser extent, olaparib - enhance PARP2 foci by preventing PARP2 exchange. This trapping of PARP2 is independent of auto-PARylation and is abolished by the R140A mutation in the WGR domain and the H415A mutation in the catalytic domain. Taken together, we found that PARP inhibitors trap PARP2 by physically stalling PARP2 on DNA via the WGR-DNA interaction while suppressing the PARP1- and PAR-dependent rapid exchange of PARP2. &nbsp;</p

ARP2/3- and resection-coupled genome reorganization facilitates translocations [preprint]

DNA end-resection and nuclear actin-based movements orchestrate clustering of double-strand breaks (DSBs) into homology-directed repair (HDR) domains. Here, we analyze how actin nucleation by ARP2/3 affects damage-dependent and -independent 3D genome reorganization and facilitates pathologic repair. We observe that DNA damage, followed by ARP2/3-dependent establishment of repair domains enhances local chromatin insulation at a set of damage-proximal boundaries and affects compartment organization genome-wide. Nuclear actin polymerization also promotes interactions between DSBs, which in turn facilitates aberrant intra- and inter-chromosomal rearrangements. Notably, BRCA1 deficiency, which decreases end-resection, DSB mobility, and subsequent HDR, nearly abrogates recurrent translocations between AsiSI DSBs. In contrast, loss of functional BRCA1 yields unique translocations genome-wide, reflecting a critical role in preventing spontaneous genome instability and subsequent rearrangements. Our work establishes that the assembly of DSB repair domains is coordinated with multiscale alterations in genome architecture that enable HDR despite increased risk of translocations with pathologic potential