Structure and mechanism of human DNA polymerase η

The variant form of the human syndrome xeroderma pigmentosum (XPV) is caused by a deficiency in DNA polymerase eta (Pol eta), a DNA polymerase that enables replication through ultraviolet-induced pyrimidine dimers. Here we report high-resolution crystal structures of human Pol eta at four consecutive steps during DNA synthesis through cis-syn cyclobutane thymine dimers. Pol eta acts like a 'molecular splint' to stabilize damaged DNA in a normal B-form conformation. An enlarged active site accommodates the thymine dimer with excellent stereochemistry for two-metal ion catalysis. Two residues conserved among Pol eta orthologues form specific hydrogen bonds with the lesion and the incoming nucleotide to assist translesion synthesis. On the basis of the structures, eight Pol eta missense mutations causing XPV can be rationalized as undermining the molecular splint or perturbing the active-site alignment. The structures also provide an insight into the role of Pol eta in replicating through D loop and DNA fragile sites

Snowmass2021 - Letter of interest cosmology intertwined IV: the age of the universe and its curvature

A precise measurement of the curvature of the Universe is of prime importance for cosmology since it could not only confirm the paradigm of primordial inflation but also help in discriminating between different early-Universe scenarios. Recent observations, while broadly consistent with a spatially flat standard Cold Dark Matter (CDM) model, show tensions that still allow (and, in some cases, even suggest) a few percent deviations from a flat universe. In particular, the Planck Cosmic Microwave Background power spectra, assuming the nominal likelihood, prefer a closed universe at more than 99% confidence level. While new physics could be at play, this anomaly may be the result of an unresolved systematic error or just a statistical fluctuation. However, since positive curvature allows a larger age of the Universe, an accurate determination of the age of the oldest objects provides a smoking gun in confirming or falsifying the current flat CDM model